Abhd6 antagonist

ABSTRACT

A drug is provided, which containing, as an active ingredient, a compound having ABHD6 inhibitory activity in prevention and/or treatment of a disease associated with ABHD6. A compound of formula (I-A) or a pharmaceutically acceptable salt thereof has ABHD6 inhibitory activity and therefore is useful as a pharmaceutical ingredient having potent ABHD6 inhibitory activity in the prevention and/or treatment of a disease associated with ABHD6: 
     
       
         
         
             
             
         
       
     
     in which all symbols represent the same meaning as the symbols described in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a bypass continuation of PCT International Application No.PCT/JP2022/016679 filed on Mar. 31, 2022, which claims priority toJapanese Patent Application No. 2021-062790 filed on Apr. 1, 2021, thecontents of all which are incorporated herein by reference in theirentirety.

FIELD

The present disclosure relates to a compound having ABHD6 inhibitoryactivity or a pharmaceutically acceptable salt thereof. Specifically,the present disclosure relates to a medicament containing a compoundrepresented by general formula (I-A), or a pharmaceutically acceptablesalt thereof (hereinafter, the compound is referred to as a compound ofthe present disclosure):

wherein all symbols represent the same meaning as the symbols describedlater.

BACKGROUND ART

ABHD6 (alpha/beta-hydrolase domain containing 6) is known as a serinehydrolase, and is one of metabolic enzymes of 2-arachidonoylglycerol(2-AG), which is an endogenous cannabinoid. 2-AG serves as a key lipidprecursor of the eicosanoid signaling pathway and also functions as anendogenous signaling lipid for the activation of cannabinoid receptors 1and 2 (CB1 and CB2, respectively). Thus, ABHD6 and 2-AG are known to beinvolved in the regulation of various physiological processes includingpain sensation, neurotransmission, inflammation, insulin secretion,brown adipogenesis, food intake, autoimmune disorders, neurologicaldiseases, and metabolic diseases (Non-Patent Document 1).

It is also known that inhibiting ABHD6 significantly reducesneuroinflammation and exerts neuroprotection in animal models oftraumatic brain injury and multiple sclerosis. It is believed thatinhibition of ABHD6 is useful for the prevention and/or treatment ofvarious inflammatory and neurological diseases without causing centralside effects by the cannabinoid system (Non-Patent Document 2).

On the other hand, Patent Document 1 states that the compoundrepresented by the following general formula (A) is a compound havingmAChR receptor antagonistic activity.

General formula (A) is as follows:

-   -   wherein ring A^(A) represents a 5- to 6-membered heteroaryl ring        having 1 to 3 heteroatoms selected from N, O, and S,    -   Q^(A) represents NR^(aA) or O,    -   mA represents 0, 1, or 2,    -   R^(1A) is selected from heteroaryl, aryl, heterocyclyl,        cycloalkyl, halogen, —OR^(bA), —NR^(CA)R^(dA) and NHCOR^(eA),    -   nA represents 1 or 2,    -   R^(2A) is selected from hydrogen, a C1-4 alkyl group, halogen,        and —OR^(fA),    -   R^(3A) is selected from hydrogen and a C1-4 alkyl group,    -   R^(4A) is selected from —(CR^(gA)R^(bA))_(pA)—Y^(A′), hydrogen,        a C1-8 alkyl group, and a C1-8 alkenyl group,    -   R^(5A) is selected from hydrogen, a C1-4 alkyl group, halogen, a        C1-4 haloalkyl group, a C1-4 alkoxy group, and a C1-4 haloalkoxy        group,    -   Y^(A′) is selected from cycloalkyl, cycloalkenyl, heterocycle,        aryl, and heteroaryl,    -   p^(A) represents an integer of 0 to 4, and the definition of        groups was partially excerpted.

In addition, it is described that the compound represented by thefollowing general formula (B) in Patent Document 2 is a compound havinga FAAH inhibitory action.

General formula (B) is as follows:

-   -   wherein R^(2B) represents hydrogen, fluorine, hydroxyl, cyano,        trifluoromethyl, a C1-6 alkyl group, a C1-6 alkoxy group, or a        NR^(8B)R^(9B) group,    -   m^(B), n^(B), o^(B) and p^(B) each independently represent        numbers ranging from 0 to 3, and each of m^(B)+o^(B) and        n^(B)+p^(B) is 4 or less,    -   A^(B) represents a covalent bond, an oxygen atom, a C1-6        alkylene group, or an —O—C1-6 alkylene group (in this case, the        terminal represented by the oxygen atom is bonded to the group        R^(IB), and the terminal represented by the alkylene group is        bonded to a bicyclic carbon),    -   R^(1B) is unsubstituted or represents R^(5B) which is        substituted with one or more R^(6B)s and/or R^(7B)s,    -   R^(5B) represents a group selected from phenyl, pyridyl,        pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl,        quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,        cinnolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl,        benzimidazolyl, benzisothiazolyl, benzisoxazolyl, indazolyl, and        benzotriazolyl,    -   R^(3B) represents hydrogen, a fluorine atom, a C1-6 alkyl group,        or a trifluoromethyl group,    -   R^(4B) represents a 5-membered heterocyclic ring selected from        furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,        isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazole,        triazolyl, and tetrazolyl, and the definition of groups was        partially excerpted.

In addition, it is described that the compound represented by thefollowing general formula (C) in Patent Document 3 is a compound havinga Ca channel inhibitory action.

General formula (C) is as follows:

-   -   wherein L^(1C) is C(O), S(O)₂, SO₂N(R⁴), C(O)O, or        —(CR^(aC)R^(bC))_(mC)—,    -   R^(1C) is alkyl, G^(1C), —CH(G^(1C))₂,        —(CR^(aC)R^(bC))_(mC)-G^(1C), —(CR^(aC)R^(bC))_(mC)—CH(G^(1C))₂,        —(CR^(eC)R^(fC))_(nC)—N(R^(5C))₂,        —(CR^(eC)R^(fC))_(nC)—N(R^(5C))—C(O)O(alkyl),        —(CR^(eC)R^(fC))_(nC)—N(R^(5C))—C(O)(alkyl) or        —(CR^(eC)R^(fC))_(nC)—N(R^(5C))—SO₂R^(6C), and    -   or L^(1C)-R^(1C) together are hydrogen, alkyl, hydroxyalkyl,        G^(1C), or —CH(G^(1c))₂,    -   L^(2C) is —(CR^(eC)R^(fC))_(pC)—, C(O), C(O)N(R^(4C)), S(O)₂,        SO₂N(R^(5C)), or C(O)O,    -   R^(2C) is alkyl, G^(2C), —C(R^(cC))(G^(2C))(G^(3C)),        —(CR^(cC)R^(dC))_(pC)-G^(2C),        —(CR^(cC)R^(dC))_(pC)—CH(G^(2C))(G^(3C)),        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—C(O)O(alkyl),        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—C(O)O-G^(2C),        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—C(O)(alkyl),        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—SO₂R^(6C),        —(CR^(gC)R^(hC))_(qC)—N(R^(4C))(R^(5C)),        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—C(O)N(R^(5C))-(alkyl) or        —(CR^(gC)R^(hC))_(qC)—N(R^(5C))—C(O)N(R^(5C))-G^(2C), and    -   or L^(2C)-R^(2C) together are alkyl, G^(2C) or        —C(R^(cC))(G^(2C))(G^(3C)),    -   G^(1C), G^(2C) and G^(3C) are each independently aryl,        cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic; G^(1C),        G^(2C) and G^(3C) are each independently unsubstituted or        substituted with one, two, three, four or five substituents; and        G^(1C) is other than quinoline, quinazolinedione or        pyridopyrimidinedione;    -   R^(3C) represents hydrogen, alkyl, haloalkyl, cycloalkyl or        cycloalkylalkyl, and the definition of groups was partially        excerpted.

However, none of the prior art documents describe or suggest that thecompound of the present disclosure has ABHD6 inhibitory activity.

RELATED DOCUMENTS Patent Documents

-   [Patent Document 1] WO 2019/089676 A-   [Patent Document 2] WO 2010/130944 A-   [Patent Document 3] WO 2010/062927 A

Non-Patent Documents

-   [Non-Patent Document 1] European Journal of Medicinal Chemistry,    Vol. 198, article No. 112353, 2020-   [Non-Patent Document 2] Journal of Neuroinflammation, Vol. 15,    article No. 9, 2018

SUMMARY Problems to be Solved

An object of the present invention is to provide a compound havinginhibitory activity on ABHD6.

Means for Solving the Problems

As a result of intensive studies to solve the above problems, thepresent inventors have found that a compound represented by generalformula (I-A) described later has potent inhibitory activity on ABHD6.

That is, one aspect of the present disclosure provides the followingembodiments and the like:

[1] A compound represented by general formula (I-A) or apharmaceutically acceptable salt thereof:

-   -   wherein    -   X¹ and X² each independently represent (1) CH, (2) CR^(X),        or (3) N, provided that at least one of X¹ and X² represents N,    -   R¹ represents a halogen atom,    -   R^(X) represents (1) a halogen atom, (2) a C1-6 alkyl group, (3)        a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6        alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   R² represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   when m is 2 or more, a plurality of R²s may be the same or        different,    -   R³ represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a        C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5)        —(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) —(C1-6        haloalkylene)-(3- to 10-membered cyclic group), wherein one to        two carbon atoms in the C1-6 alkyl group, the C1-6 haloalkyl        group, the C1-6 alkylene, and the C1-6 haloalkylene may be        replaced with an oxygen atom or an optionally oxidized sulfur        atom,    -   the 3- to 10-membered cyclic group in R³ may be substituted with        one to five R³⁰¹s,    -   R³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C1-4 haloalkyl group, (5) a C1-4        haloalkoxy group, (6) COOR³⁰², (7) CONR³⁰³R³⁰⁴, (8) a C3-6        cycloalkyl group, (9) a hydroxyl group, (10) a nitro group, (11)        a cyano group, (12) —NR³⁰⁵R³⁰⁶, (13) —SR³⁰⁷, (14) —SOR³⁰⁸, (15)        —SO₂R³⁰⁹, or (16) an oxo group,    -   when two or more R³⁰¹s are substituted, a plurality of R³⁰¹s may        be the same or different,    -   R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, or R³⁰⁹ each        independently represent (1) a hydrogen atom or (2) a C1-4 alkyl        group,    -   when R² represents (2) to (9) in R², and R³ represents a C1-6        alkyl group, R² and R³, together with an atom to which R² and R³        are bonded, may form a 5- to 6-membered cyclic group,    -   R⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy        group,    -   when n is 2 or more, a plurality of R⁴s may be the same or        different,    -   when two R⁴s present on the same carbon atom represent a C1-6        alkyl group, the two R⁴s, together with a carbon atom to which        the two R⁴s are bonded, may form a C3-6 cycloalkyl group,    -   ring 1 represents a 3- to 15-membered cyclic group,    -   R^(5-A) represents (1) a halogen atom, (2) a C1-6 alkyl        group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a        C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6        alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6        acyl group, (10) a 3- to 6-membered cyclic group, (11)        -L^(R5)-(3- to 6-membered cyclic group), (12) a hydroxyl        group, (13) a nitro group, (14) a cyano group, (15) an oxo        group, (16) —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵,        or (19) —SO₂NR⁵⁰⁶R⁵⁰⁷, wherein one to two carbon atoms in the        C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl        group, the C1-6 alkoxy group, the C1-6 alkylthio group, the C1-6        alkylsulfinyl group, the C1-6 alkylsulfonyl group, and the C2-6        acyl group may be replaced with an oxygen atom or an optionally        oxidized sulfur atom,    -   when p is 2 or more, a plurality of R^(5-A)s may be the same or        different,    -   the groups (2) to (11) in R^(5-A) may be substituted with one to        nine R⁵⁰⁸s,    -   R⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6        cycloalkyl group, (6) a hydroxyl group, or (7) —NR⁵⁰⁹R⁵¹⁰,    -   when two or more R⁵⁰¹s are substituted, a plurality of R⁵⁰⁸s may        be the same or different,    -   L^(R5) represents (1) —O—, (2) —(C1-4 alkylene)-, (3) —O—(C1-4        alkylene)-, (4) —(C1-4 alkylene)-O—, (5) —NR⁵¹¹— or (6) —SO₀₋₂—,    -   R⁵⁰¹, R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, R⁵⁰⁹, R⁵¹⁰, or R⁵¹¹        each independently represent (1) a hydrogen atom, (2) a C1-6        alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl        group,    -   m represents an integer of 0 to 2,    -   n represents an integer of 0 to 5, and    -   p represents an integer of 0 to 5.

[2] A compound represented by general formula (I) or a pharmaceuticallyacceptable salt thereof:

-   -   wherein R⁵ represents (1) a halogen atom, (2) a C1-6 alkyl        group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a        C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6        alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6        acyl group, (10) a 3- to 6-membered cyclic group, (11)        -L^(R5)-(3- to 6-membered cyclic group), (12) a hydroxyl        group, (13) a nitro group, (14) a cyano group, (15) an oxo        group, (16) —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵,        or (19) —SO₂NR⁵⁰⁶R⁵⁰⁷,    -   when p is two or more, a plurality of R⁵s may be the same or        different,    -   the groups (2) to (11) in R⁵ may be substituted with one to nine        R⁵⁰⁸s, and    -   other symbols represent the same meaning as the symbols        described in the above [1].

[3] A pharmaceutical composition containing the compound or thepharmaceutically acceptable salt thereof according to the above [1] or[2] as an active ingredient, and a pharmaceutically acceptable carrier

[4] The pharmaceutical composition according to the above [3], which isan ABHD6 inhibitor.

Effects of the Invention

The compound of the present disclosure has inhibitory activity on ABHD6,and thus the compound of the present disclosure is useful as an agentfor preventing and/or treating a disease associated with ABHD6.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present disclosure will be described in detail.

In the present specification, examples of the halogen atom includefluorine, chlorine, bromine, and iodine atoms.

In the present specification, examples of the C1-4 alkyl group includemethyl, ethyl, propyl, butyl groups, and isomers thereof.

In the present specification, examples of the C1-6 alkyl group includemethyl, ethyl, propyl, butyl, pentyl, hexyl groups, and isomers thereof.

In the present specification, examples of the C2-6 alkenyl group includeethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl,hexadienyl groups, and isomers thereof.

In the present specification, examples of the C2-6 alkynyl group includeethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl,hexadiynyl groups, and isomers thereof.

In the present specification, examples of the C1-4 alkylene includemethylene, ethylene, propylene, butylene, and isomers thereof.

In the present specification, examples of the C1-6 alkylene includemethylene, ethylene, propylene, butylene, pentylene, hexylene, andisomers thereof.

In the present specification, the C1-4 haloalkyl group means, forexample, an alkyl group substituted with one or more halogen atoms.Specific examples of the C1-4 haloalkyl group include a fluoromethylgroup, a chloromethyl group, a bromomethyl group, an iodomethyl group, adifluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutylgroup, and isomers thereof.

In the present specification, the C1-6 haloalkyl group means, forexample, an alkyl group substituted with one or more halogen atoms.Specific examples of the C1-6 haloalkyl group include a fluoromethylgroup, a chloromethyl group, a bromomethyl group, an iodomethyl group, adifluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutylgroup, a 5,5,5-trifluoropentyl group, a 6,6,6-trifluorohexyl group, andisomers thereof.

In the present specification, the C1-6 haloalkylene means, for example,alkylene substituted with one or more halogen atoms. Specific examplesof the C1-6 haloalkylene include fluoromethylene, chloromethylene,bromomethylene, iodomethylene, difluoromethylene, 1-fluoroethylene,2-fluoroethylene, 2-chloroethylene, pentafluoroethylene,1-fluoropropylene, 2-chloropropylene, 3-fluoropropylene,3-chloropropylene, 4-bromobutylene, 5-fluoropentylene, 6-fluorohexylene,and isomers thereof.

In the present specification, the C2-6 haloalkenyl group means, forexample, an alkenyl group substituted with one or more halogen atoms.Specific examples of the C2-6 haloalkenyl group include a1-fluoroethenyl group, a 2-fluoroethenyl group, a 2-chloroethenyl group,a 1-fluoropropenyl group, a 2-chloropropenyl group, a 3-fluoropropenylgroup, a 3-chloropropenyl group, a 4-bromobutenyl group, a5,5,5-trifluoropentenyl group, a 6,6,6-trifluorohexenyl group, andisomers thereof.

In the present specification, the C2-6 haloalkynyl group means, forexample, an alkynyl group substituted with one or more halogen atoms.Specific examples of the C2-6 haloalkynyl group include a2-fluoroethynyl group, a 2-chloroethynyl group, a 3-fluoropropynylgroup, a 3-chloropropynyl group, a 4-bromobutynyl group, a5,5,5-trifluoropentynyl group, a 6,6,6-trifluorohexynyl group, andisomers thereof.

In the present specification, examples of the C1-4 alkoxy group includesmethoxy, ethoxy, propoxy, butoxy groups, and isomers thereof.

In the present specification, examples of the C1-6 alkoxy group includesmethoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, andisomers thereof.

In the present specification, the C1-4 haloalkoxy group means, forexample, an alkoxy group substituted with one or more halogen atoms.Specific examples of the C1-4 haloalkoxy group include a fluoromethoxygroup, a chloromethoxy group, a bromomethoxy group, an iodomethoxygroup, a difluoromethoxy group, a trifluoromethoxy group, a1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, apentafluoroethoxy group, a 1-fluoropropoxy group, a 2-chloropropoxygroup, a 3-fluoropropoxy group, a 3-chloropropoxy group, a4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, and isomers thereof.

In the present specification, the C1-6 haloalkoxy group means, forexample, an alkoxy group substituted with one or more halogen atoms.Specific examples of the C1-6 haloalkoxy group include a fluoromethoxygroup, a chloromethoxy group, a bromomethoxy group, an iodomethoxygroup, a difluoromethoxy group, a trifluoromethoxy group, a1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, apentafluoroethoxy group, a 1-fluoropropoxy group, a 2-chloropropoxygroup, a 3-fluoropropoxy group, a 3-chloropropoxy group, a4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, a5,5,5-trifluoropentyloxy group, a 6,6,6-trifluorohexyloxy group, andisomers thereof.

In the present specification, examples of the C1-6 alkylthio groupinclude methylthio, ethylthio, propylthio, butylthio, pentylthio,hexylthio groups, and isomers thereof.

In the present specification, examples of the C1-6 alkylsulfinyl groupinclude methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl,pentylsulfinyl, hexylsulfinyl groups, and isomers thereof.

In the present specification, examples of the C1-6 alkylsulfonyl groupinclude methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,pentylsulfonyl, hexylsulfonyl groups, and isomers thereof.

In the present specification, examples of the C3-6 cycloalkyl groupinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

In the present specification, examples of the C2-6 acyl group includeethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl groups, and isomersthereof.

In the present specification, the 3- to 6-membered cyclic grouprepresents a C3-6 carbocyclic ring and a 3- to 6-membered heterocyclicring.

In the present specification, examples of the C3-6 carbocyclic ringinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene,cyclohexadiene, and benzene rings.

In the present specification, examples of the 3- to 6-memberedheterocyclic ring include aziridine, azetidine, oxirane, oxetane,thiirane, thietane, pyrrole, imidazole, triazole, tetrazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene,thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine,pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxadiazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole,tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane,and dithiane rings.

In the present specification, the 5- to 6-membered cyclic grouprepresents a C5-6 carbocyclic ring and a 5- to 6-membered heterocyclicring.

In the present specification, examples of the C5-6 carbocyclic ringinclude cyclopentane, cyclohexane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene, and benzene rings.

In the present specification, examples of the 5- to 6-memberedheterocyclic ring include pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran,thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine,thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxadiazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole,tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane,and dithiane rings.

In the present specification, the 3- to 10-membered cyclic grouprepresents a C3-10 carbocyclic ring and a 3- to 10-membered heterocyclicring.

In the present specification, examples of the C3-10 carbocyclic ringinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene,cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indan, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hexene,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene,bicyclo[3.2.1]octane, and bicyclo[3.2.1]octene rings.

In the present specification, examples of the 3- to 10-memberedheterocyclic ring include the 3- to 6-membered heterocyclic rings, andazepine, diazepine, oxepin, thiepin, oxazepine, oxadiazepine,thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine,pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan,benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine,perhydroazepine, dihydrodiazepine, tetrahydrodiazepine,perhydrodiazepine, dihydrooxepin, tetrahydrooxepin, perhydrooxepin,dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dioxaindane, benzodioxane,chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane,oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane,thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane,oxazaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane,thieno[3,2-c]pyrazole, thieno[2,3-c]pyrazole, thieno[2,3-d]thiazole,thieno[2,3-d][1.2.3]triazole, dihydropyrano[3,4-d]thiazole,dihydrothieno[2,3-b]pyran, dihydrothieno[3,2-c]pyran,dihydrothieno[3,2-b]pyran, dihydrothieno[3,2-c]thiopyran,tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, andthieno[3,2-c]pyridine rings.

In the present specification, the 3- to 15-membered cyclic grouprepresents a C3-15 carbocyclic ring and a 3- to 15-membered heterocyclicring.

In the present specification, examples of the C3-15 carbocyclic ringinclude the C3-10 carbocyclic rings, and heptalene, biphenylene,as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene,phenalene, phenanthrene, and anthracene rings.

In the present specification, examples of the 3- to 15-memberedheterocyclic ring include the 3- to 10-membered heterocyclic rings andbenzoxadiazepine, benzothiadiazepine, benzoxazepine, benzothiazepine,benzodiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine,benzoxepin, benzothiepine, benzazepine, dihydrobenzazepine,tetrahydrobenzazepine, perimidine, β-carboline, dihydrocarbazole,tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole,dibenzofuran, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenazine, phenanthroline, xanthene,dihydroacridine, tetrahydroacridine, acridine, phenanthridine, anddihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole rings.

In the present specification, “one to two carbon atoms may be replacedwith an oxygen atom or an optionally oxidized sulfur atom” means thatone or two carbon atoms (—CH₂—) at a structurally possible position inthe substituent may be replaced with an oxygen atom (—O—) or anoptionally oxidized sulfur atom (—S—, —SO—, or —SO₂—). Specific examplesof such a group in the case of the C1-6 alkyl group include a CH₃—O—CH₂—group, a CH₃—CH₂—O—CH₂— group, a CH₃—O—CH₂—CH₂— group, aCH₃—O—CH₂—CH₂—CH₂— group, a CH₃—CH₂—O—CH₂—CH₂— group.

In the present disclosure, X¹ and X² are preferably N.

In the present disclosure, R¹ is preferably a chlorine atom or a bromineatom.

In the present disclosure, R² is preferably a halogen atom, a C1-6 alkylgroup, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group,and more preferably a chlorine atom, a methoxy group, a trifluoromethylgroup, or a cyano group.

In the present disclosure, R^(X) is preferably a halogen atom, a C1-6alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyanogroup, and more preferably a chlorine atom, a methoxy group, atrifluoromethyl group, or a cyano group.

In the present disclosure, R³ is preferably a hydrogen atom, a C1-6alkyl group, a C1-6 haloalkyl group, a 3- to 10-membered cyclic group,or —CH₂-(3- to 10-membered cyclic group), and more preferably a hydrogenatom, a C1-6 alkyl group, a C1-6 haloalkyl group, a cyclopropyl group,—CH₂-benzene, —CH₂-pyridine, or —CH₂-imidazo[2,1-b]thiazole.

In the present disclosure, R⁴ is preferably a halogen atom or a C1-6alkyl group, and more preferably a fluorine atom or a methyl group.

In the present disclosure, ring 1 is preferably a 3- to 10-memberedcyclic group or a ring structure selected from the group consisting of:

-   -   wherein the * mark represents a bonding position with a carbonyl        group.

Ring 1 is more preferably a ring structure selected from the groupconsisting of:

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-A) or R⁵.

Ring 1 is still more preferably a ring structure selected from the groupconsisting of:

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-A) or R⁵.

In the present disclosure, R⁵ is preferably a halogen atom, a C1-6 alkylgroup, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxygroup, a 3- to 6-membered cyclic group, an oxo group, —NR⁵⁰¹R⁵⁰², or—COOR⁵⁰³, more preferably a C1-6 alkyl group, a C1-6 alkoxy group, aC1-6 haloalkyl group, a C1-6 haloalkoxy group, a cyclopropyl group, afuran ring, an N-methylpyrazole ring, an oxo group, a dimethylaminogroup, or —COOCH₃, and still more preferably a C1-6 alkyl group, a C1-6haloalkyl group, a C1-6 haloalkoxy group, or a cyclopropyl group.

In the present disclosure, R^(5-A) is preferably a halogen atom, a C1-6alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6haloalkoxy group, a 3- to 6-membered cyclic group, an oxo group,—NR⁵⁰¹R⁵⁰², or —COOR⁵⁰³, more preferably a C1-6 alkyl group, a C1-6alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, acyclopropyl group, a furan ring, an N-methylpyrazole ring, an oxo group,a dimethylamino group, or —COOCH₃, and still more preferably a C1-6alkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or acyclopropyl group.

In the present disclosure, m is preferably 0 or 1.

In the present disclosure, n is preferably 0, 1, or 2.

In the present disclosure, p is preferably 0, 1, or 2.

In the present disclosure, the compound represented by general formula(I-A) or general formula (I) is preferably a compound represented bygeneral formula (I-1):

-   -   wherein R^(3-a) represents (1) a hydrogen atom, (2) a C1-6 alkyl        group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group,        or (5) —CH₂-Q,    -   Q represents (1) benzene, (2) pyridine, or (3)        imidazo[2,1-b]thiazole,    -   ring 1-a represents a ring structure selected from the group        consisting of the following ring structures;

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-a),    -   R^(5-a) represents (1) a C1-6 alkyl group, (2) a C1-6 alkoxy        group, (3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy        group, (5) a cyclopropyl group, (6) a furan ring, (7) an        N-methylpyrazole ring, (8) an oxo group, (9) a dimethylamino        group, or (10) —COOCH₃, and other symbols represent the same        meaning as the above symbols.

In the present disclosure, the compound represented by general formula(I-A) is preferably a combination of the preferred definitions of X¹,X², R¹, R², R³, R⁴, R^(5-A), ring 1, n, m, and p.

In the present disclosure, the compound represented by general formula(I) is preferably a combination of the preferred definitions of X¹, X²,R¹, R², R³, R⁴, R⁵, ring 1, n, m, and p.

In the present disclosure, another embodiment of the compoundrepresented by general formula (I-A) or general formula (I) is mostpreferably an example compound described in Examples described later ora pharmaceutically acceptable salt thereof.

All isomers are included in the present disclosure unless otherwiseindicated. For example, the alkyl group, the alkoxy group, the alkylenegroup, and the like include linear groups and branched groups thereof.In addition, isomers (E-, Z-, cis-, and trans-forms) in a double bond, aring, and a fused ring, isomers (R-, S-forms, α-, β-forms, enantiomer,and diastereomer) due to the presence of an asymmetric carbon, opticallyactive substances (D-, L-, d-, and l-forms) having optical rotation,polar substances obtained through chromatographic separation(high-polarity substances and low-polarity substances), equilibriumcompounds, rotational isomers, mixtures of these at an appropriateratio, and racemic mixtures are all included in the present disclosure.In addition, all isomers by tautomerism are also included in the presentdisclosure.

In the present specification, the compound described as “rel-” in thecompound name indicates that the steric configurations of a plurality ofstereogenic centers are relative configurations.

In the present disclosure, unless otherwise specified, the symbol:

-   -   represents that a substituent is bonded to the back side of the        paper surface (that is, α-configuration), the symbol:    -   represents that a substituent is bonded to the front side of the        paper surface (that is, β-configuration), and the symbol:    -   represents a mixture of α- and β-configurations at an        appropriate ratio, as would be apparent to those skilled in the        art.

[Salt]

The compound represented by general formula (I-A) is converted into asalt by a known method.

The salt is a pharmaceutically acceptable salt.

The salt is preferably water-soluble.

Examples of the pharmaceutically acceptable salt include, acid additionsalts, alkali metal salts, alkaline earth metal salts, ammonium salts,and amine salts.

Examples of the acid addition salt include inorganic acid salts such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, andnitrate, or organic acid salts such as acetate, lactate, tartrate,benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate, andgluconate.

Examples of the alkali metal salt include a potassium salt and a sodiumsalt.

Examples of the alkaline earth metal salt include a calcium salt and amagnesium salt.

Examples of the ammonium salt include a tetramethylammonium salt.

Examples of the amine salt include a triethylamine salt, a methylaminesalt, a dimethylamine salt, a cyclopentylamine salt, a benzylamine salt,a phenethylamine salt, a piperidine salt, a monoethanolamine salt, adiethanolamine salt, a tris(hydroxymethyl)aminomethane salt, a lysinesalt, an arginine salt, and an N-methyl-D-glucamine salt.

In addition, the compound of the present disclosure can be convertedinto an N-oxide by any method. The N-oxide represents a compoundobtained by oxidizing a nitrogen atom of the compound represented bygeneral formula (I-A).

The compound represented by general formula (I-A) and a pharmaceuticallyacceptable salt thereof may exist in a non-solvated form or in asolvated form with a pharmaceutically acceptable solvent such as wateror ethanol. The solvate is preferably a hydrate. The compoundrepresented by general formula (I-A) and a pharmaceutically acceptablesalt thereof can be converted into a solvate.

The compound represented by general formula (I-A) can form a cocrystalwith an appropriate cocrystal former. The cocrystal is preferably apharmaceutically acceptable cocrystal that is formed with apharmaceutically acceptable cocrystal former. The cocrystal is typicallydefined as a crystal in which two or more different molecules are formedby intermolecular interaction that is different from ionic bonds. Thecocrystal may be a complex of a neutral molecule and a salt. Thecocrystal can be prepared by a known method, for example, by meltingcrystallization, recrystallization from a solvent, or physicallypulverizing the components together. Suitable cocrystal formers includethose described in WO 2006/007448.

In the present disclosure, all references to the compound of the presentdisclosure include a compound represented by general formula (I-A), apharmaceutically acceptable salt thereof, an N-oxide thereof, a solvatethereof (for example, a hydrate), or a cocrystal thereof, or an N-oxideof a pharmaceutically acceptable salt of the compound represented bygeneral formula (I-A), a solvate thereof (for example, a hydrate), or acocrystal thereof.

[Prodrug]

The prodrug of the compound represented by general formula (I-A) refersto a compound that is converted into the compound represented by generalformula (I-A) through a reaction with an enzyme, gastric acid, or thelike in vivo. Examples of the prodrug of the compound represented bygeneral formula (I-A) include: compounds in which an amino group isacylated, alkylated, or phosphorylated (for example, compounds in whichthe amino group of the compound represented by general formula (I-A) iseicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidyl methylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated, or the like) in the case where thecompound represented by general formula (I-A) has an amino group;compounds in which a hydroxyl group is acylated, alkylated,phosphorylated, or borated (for example, compounds in which the hydroxylgroup of the compound represented by general formula (I-A) isacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated, dimethylaminomethylcarbonylated, or the like)in the case where the compound represented by general formula (I-A) hasa hydroxyl group; and compounds in which a carboxy group is esterifiedor amidated (for example, compounds in which the carboxy group of thecompound represented by general formula (I-A) is ethyl esterified,phenyl esterified, carboxymethyl esterified, dimethylaminomethylesterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethylesterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidated, or thelike) in the case where the compound represented by general formula(I-A) has a carboxy group. These compounds can be produced by a methodknown per se. The prodrug of the compound represented by general formula(I-A) may be either a hydrate or a non-hydrate. In addition, the prodrugof the compound represented by general formula (I-A) may be a compoundthat is converted into the compound represented by general formula (I-A)under a physiological condition as described in “Development ofPharmaceuticals”, Vol. 7, “Molecular Design”, pp. 163 to 198, publishedby Hirokawa Shoten, 1990.

Furthermore, each atom constituting the compound represented by generalformula (I-A) may be substituted with an isotope thereof (for example,²H, ³H, ¹¹C ¹³C, ¹⁴C, ¹⁵N, ¹⁶N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁷⁷Br, and¹²⁵I) or the like.

[Method for Producing Compound of Present Disclosure]

The compound of the present disclosure can be produced by appropriatelyimproving known methods, for example, methods shown below, methodsequivalents thereto, the method described in Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, 3rd Edition(Richard C. Larock, John Wiley & Sons Inc, 2018), the methods describedin Examples or the like, and using a combination thereof. A salt may beused as the starting material thereof. The order of carrying out eachreaction can be appropriately changed depending on the protecting groupintroduced and reaction conditions.

In addition, a compound having an amino group, a carboxyl group, or ahydroxyl group can be produced, if necessary, by performing a knowndeprotection reaction after an appropriate reaction step, by using acompound protected with a protecting group commonly used for thesegroups. The protecting group is, for example, the protecting groupsdescribed in T. W. Greene, Protective Groups in Organic Synthesis,Wiley, New York, 5th Edition, 2014.

Examples of the protecting group of a carboxyl group include methyl,ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl,p-methoxybenzyl, trityl, and 2-chlorotrityl.

Examples of the protecting group of an amino group or a tetrazolyl groupinclude a benzyloxycarbonyl group, a tert-butoxycarbonyl group, anallyloxycarbonyl (Alloc) group, a 1-methyl-1(4-biphenyl)ethoxycarbonyl(Bpoc) group, a trifluoroacetyl group, a 9-fluorenylmethoxycarbonylgroup, a benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl(BOM) group, and a 2-(trimethylsilyl)ethoxymethyl (SEM) group.

Examples of the protecting group of a hydroxyl group or hydroxamic acidinclude methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE),methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl(TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl(Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and2,2,2-trichloroethoxycarbonyl (Troc).

The deprotection reaction is known, and can be performed by, forexample, the following methods: (1) a deprotection reaction by alkalinehydrolysis;

-   -   (2) a deprotection reaction under an acidic condition;    -   (3) a deprotection reaction by hydrogenolysis;    -   (4) a deprotection reaction of a silyl group;    -   (5) a deprotection reaction by using a metal; and    -   (6) a deprotection reaction by using a metal complex.

These methods are specifically described as follows.

-   -   (1) The deprotection reaction by alkaline hydrolysis is        performed, for example, at 0 to 40° C., in an organic solvent        (for example, methanol, tetrahydrofuran (hereinafter, THF), and        dioxane), by using a hydroxide of an alkali metal (for example,        sodium hydroxide, potassium hydroxide, and lithium hydroxide), a        hydroxide of an alkaline earth metal (for example, barium        hydroxide and calcium hydroxide), a carbonate (for example,        sodium carbonate and potassium carbonate), or an aqueous        solution or mixture thereof.    -   (2) The deprotection reaction under an acidic condition is        performed, for example, at 0 to 100° C., in an organic solvent        (for example, dichloromethane, chloroform, dioxane, ethyl        acetate, methanol, isopropyl alcohol, THF, and anisole), in an        organic acid (for example, acetic acid, trifluoroacetic acid,        methanesulfonic acid, and p-tosylic acid) or an inorganic acid        (for example, hydrochloric acid and sulfuric acid), or a mixture        thereof (for example, hydrogen bromide/acetic acid), in the        presence or absence of 2,2,2-trifluoroethanol.    -   (3) The deprotection reaction by hydrogenolysis is performed,        for example, at 0 to 200° C., in a solvent (for example, an        ether-based solvent such as THF, dioxane, dimethoxyethane, and        diethyl ether; an alcohol-based solvent such as methanol and        ethanol; a benzene-based solvent such as benzene and toluene; a        ketone-based solvent such as acetone and methyl ethyl ketone; a        nitrile-based solvent such as acetonitrile; an amide-based        solvent such as N,N-dimethylformamide (hereinafter, DMF); water,        ethyl acetate, acetic acid, or a mixed solvent of two or more        thereof), in the presence of a catalyst (for example,        palladium-carbon, palladium black, palladium hydroxide-carbon,        platinum oxide, and Raney nickel), under a hydrogen atmosphere        under normal pressure or pressure, or in the presence of        ammonium formate.    -   (4) The deprotection reaction of a silyl group is performed, for        example, at 0 to 40° C., in an organic solvent (for example, THE        and acetonitrile) miscible with water, by using        tetrabutylammonium fluoride. In addition, the deprotection        reaction is performed, for example, at −10 to 100° C., in an        organic acid (for example, acetic acid, trifluoroacetic acid,        methanesulfonic acid, and p-tosylic acid) or an inorganic acid        (for example, hydrochloric acid and sulfuric acid), or a mixture        thereof (for example, hydrogen bromide/acetic acid).    -   (5) The deprotection reaction using a metal is performed, for        example, at 0 to 40° C., in an acidic solvent (for example, a        mixed solution of acetic acid, a buffer solution having a pH of        4.2 to 7.2, or a solution thereof with an organic solvent such        as THF), in the presence of powdery zinc while applying        ultrasonic waves if necessary.    -   (6) The deprotection reaction using a metal complex is        performed, for example, at 0 to 40° C., in an organic solvent        (for example, dichloromethane, DMF, THF, ethyl acetate,        acetonitrile, dioxane, and ethanol), water, or a mixed solvent        thereof, in the presence of a trapping reagent (for example,        tributyltin hydride, triethylsilane, dimedone, morpholine,        diethylamine, and pyrrolidine), an organic acid (for example,        acetic acid, formic acid, and 2-ethylhexanoic acid), and/or an        organic acid salt (for example, sodium 2-ethylhexanoate and        potassium 2-ethylhexanoate), in the presence or absence of a        phosphine-based reagent (for example, triphenylphosphine), by        using a metal complex (for example, tetrakistriphenylphosphine        palladium(0), bis(triphenylphosphine)palladium(II) dichloride,        palladium(II) acetate, and tris(triphenylphosphine)rhodium(I)        chloride).

The compound represented by general formula (I-A) can be produced byReaction Scheme 1.

-   -   wherein PG represents a protecting group of an amino group, Y        represents a halogen atom, Z represents a halogen atom, and        other symbols represent the same meaning as described above.

In Reaction Scheme 1, Reaction 1-1 is a halogen substitution reaction ora cross-coupling reaction. The halogen substitution reaction is known,and is performed, for example, through reaction at 0 to 200° C., in anorganic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane,diethyl ether, THF, methyl t-butyl ether, and the like), in the presenceof a base (sodium ethylate, sodium hydroxide, potassium hydroxide,triethylamine, diisopropylethylamine, sodium carbonate, sodiumbicarbonate, potassium carbonate, cesium carbonate, tripotassiumphosphate, cesium fluoride, barium hydroxide, tetrabutylammoniumfluoride, and the like), or an aqueous solution or mixture thereof.

The cross-coupling reaction is known, and is performed, for example,through reaction at room temperature to 120° C., in an organic solvent(benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile,dimethoxyethane, acetone, and the like), in the presence of a base(sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine,sodium carbonate, sodium bicarbonate, potassium carbonate, cesiumcarbonate, thallium carbonate, tripotassium phosphate, cesium fluoride,barium hydroxide, tetrabutylammonium fluoride, and the like), or anaqueous solution or mixture thereof and a catalyst(tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),bis(triphenylphosphine)palladium dichloride (PdCl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,1,1′-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl₂(dppf)₂),diallylpalladium dichloride (PdCl₂(allyl)₂),phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh₃)₂), and thelike).

In Reaction Scheme 1, Reaction 1-2 is an N-alkylation reaction. TheN-alkylation reaction is known, and is performed, for example, throughreaction at 0 to 100° C., in an organic solvent (DMF, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, THF, methylt-butyl ether, and the like), in the presence of a hydroxide of analkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide,and the like), a hydroxide of an alkaline earth metal (barium hydroxide,calcium hydroxide, and the like), a carbonate (sodium carbonate,potassium carbonate, and the like), or an aqueous solution or mixturethereof.

In Reaction Scheme 1, Reaction 1-3 is a deprotection reaction, and canbe performed in the same manner as described above.

In Reaction Scheme 1, Reaction 1-4 is an amidation reaction. Theamidation reaction is known, and examples thereof include:

-   -   (1) a method using an acid halide;    -   (2) a method using a mixed acid anhydride; and    -   (3) a method using a condensing agent. These methods are        specifically described as follows.    -   (1) The method using an acid halide is performed, for example,        by reacting a carboxylic acid with an acid halogenating agent        (oxalyl chloride, thionyl chloride, and the like) at −20° C. in        an organic solvent (chloroform, dichloromethane, diethyl ether,        THF, and the like) or in the absence of a solvent to reflux        temperature, and reacting the obtained acid halide with an amine        at 0 to 40° C. in the presence of a base (pyridine,        triethylamine, dimethylaniline, dimethylaminopyridine,        diisopropylethylamine, and the like) in an organic solvent        (chloroform, dichloromethane, diethyl ether, THF, and the like).        Alternatively, the method can also be performed by reacting the        obtained acid halide with an amine at 0 to 40° C. by using an        alkali aqueous solution (sodium bicarbonate water, sodium        hydroxide solution, and the like) in an organic solvent        (dioxane, THF, and the like).    -   (2) The method using a mixed acid anhydride is performed, for        example, by reacting a carboxylic acid with an acid halide        (pivaloyl chloride, tosyl chloride, mesyl chloride, and the        like) or an acid derivative (ethyl chloroformate, isobutyl        chloroformate, and the like) at 0 to 40° C. in an organic        solvent (chloroform, dichloromethane, diethyl ether, THF, and        the like) or in the absence of a solvent in the presence of a        base (pyridine, triethylamine, dimethylaniline,        dimethylaminopyridine, diisopropylethylamine, and the like), and        reacting the obtained mixed acid anhydride with an amine at 0 to        40° C. in an organic solvent (chloroform, dichloromethane,        diethyl ether, THF, and the like).    -   (3) The method using a condensing agent is performed, for        example, by reacting a carboxylic acid with an amine at 0 to 40°        C., in an organic solvent (chloroform, dichloromethane, DMF,        diethyl ether, THF, and the like) or in the absence of a        solvent, in the presence or absence of a base (pyridine,        triethylamine, dimethylaniline, dimethylaminopyridine, and the        like), by using a condensing agent (1,3-dicyclohexylcarbodiimide        (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),        1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium        iodine, 1-propylphosphonic acid cyclic anhydride        (1-propanephosphonic acid cyclic anhydride, propyl phosphonic        acid (PPA), or the like), and the like,        0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate (HATU), in the presence or absence of        1-hydroxybenztriazole (HOBt).

All of these reactions (1), (2), and (3) are desirably performed underan inert gas (argon, nitrogen, or the like) atmosphere under ananhydrous condition.

The compound represented by general formula 1a can be produced byReaction Scheme 2.

In Reaction Scheme 2, all symbols represent the same meaning as thesymbols described above.

In Reaction Scheme 2, Reaction 2-1 is a cyclization reaction, and isperformed, for example, at 0 to 100° C., in an organic solvent (DMF,dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF,methyl t-butyl ether, and the like), in the presence of an acid(trifluoroacetic acid and the like).

In Reaction Scheme 2, Reaction 2-2 is a reduction reaction of a carbonylgroup, and is performed at 0 to 40° C., in an organic solvent(dichloroethane, dichloromethane, DMF, THF, a mixture thereof, and thelike), in the presence of a reducing agent (such as sodium borohydride).

In Reaction Scheme 2, Reaction 2-3 is a tosylation reaction, and can beperformed by reacting p-toluenesulfonyl chloride at 0 to 100° C., in anorganic solvent (for example, dichloromethane, diethyl ether, THF,acetonitrile, benzene, toluene), in the presence of a base (for example,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, anddiisopropylethylamine).

In Reaction Scheme 2, Reaction 2-4 is an azidation reaction, and can beperformed, for example, by reacting sodium azide at 0 to 100° C., in anorganic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane,diethyl ether, THF, methyl t-butyl ether, and the like).

In Reaction Scheme 2, Reaction 2-5 is a reduction reaction of an azidegroup, and is performed at 0 to 200° C., in an organic solvent (forexample, THF, dioxane, dimethoxyethane, diethyl ether, methanol,ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile,DMF, ethyl acetate, acetic acid, or a mixed solvent of two or morethereof), in the presence of a hydrogenation catalyst (palladium-carbon,palladium black, palladium, palladium hydroxide, platinum dioxide,platinum-carbon, nickel, Raney nickel, ruthenium chloride, and thelike), in the presence or absence of an acid (hydrochloric acid,sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid,acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid,formic acid, and the like), under a hydrogen atmosphere under normalpressure or pressure.

In each reaction in the present specification, the compounds representedby general formula 1b, general formula 1d, general formula 1g, generalformula 2a, and general formula 2b used as starting materials are known,or can be easily produced by combining known methods, for example, themethods described in Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 3rd Edition (Richard C. Larock, JohnWiley & Sons Inc, 2018) and the like, or methods obtained by partiallymodifying known methods or the like.

Among the compounds of the present disclosure, a compound having opticalactivity can be produced by using a starting material or reagent havingoptical activity, or by optically separating a racemic intermediate andthen converting to the present disclosure compound therefrom, oroptically separating a racemic form of the compound of the presentdisclosure.

This optical separation is known, and examples thereof include a methodin which a salt, a complex, or the like is formed with another opticallyactive compound, and then a target compound is isolated afterrecrystallization or directly separated using a chiral column or thelike.

In the reactions in the present specification, a reaction involvingheating can be performed using a water bath, an oil bath, a sand bath,or a microwave, as would be apparent to those skilled in the art.

In the reactions in the present specification, a solid-phase supportedreagent that is supported on a polymer (for example, polystyrene,polyacrylamide, polypropylene, polyethylene glycol, and the like) may beappropriately used.

In the reactions in the present specification, the reaction product canbe purified by ordinary purification means, for example, distillationunder normal pressure or reduced pressure, high-performance liquidchromatography using silica gel or magnesium silicate, thin-layerchromatography, methods using an ion-exchange resin or a scavengerresin, column chromatography, washing, and recrystallization. Thepurification may be performed for each reaction or may be performedafter completion of some reactions.

[Toxicity]

The toxicity of the compound of the present disclosure is low, andtherefore can be used as a medicament safely.

[Application to Medicament]

The compound of the present disclosure has inhibitory activity on ABHD6,and thus the compound of the present disclosure is useful as an agentfor preventing and/or treating diseases associated with ABHD6, forexample, pain, neurological diseases, inflammatory diseases, autoimmunediseases, metabolic diseases, and malignant tumors.

More specifically, examples of the pain include pain associated withosteoarthritis, cancer pain, pain associated with chemotherapy, chroniclow back pain, low back pain associated with osteoporosis, fracturepain, pain associated with rheumatoid arthritis, neuropathic pain,post-herpetic pain, pain associated with diabetic neuropathy, painassociated with fibromyalgia, pain associated with pancreatitis, painassociated with interstitial cystitis or bladder pain syndrome, painassociated with endometriosis, pain associated with irritable bowelsyndrome, migraine, and pain associated with pulpitis.

Examples of the neurological disease include tremor, dyskinesia,dystonia, spasticity, compressive and obsessive behavior, depression,mental disorders including anxiety disorder (for example, panicdisorder, acute stress disorder, post-traumatic stress disorder,obsessive-compulsive disorder, agoraphobia, social phobia), mooddisorder, epilepsy, traumatic brain injury, spinal cord injury, multiplesclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease,Alzheimer's disease, and sleep disorder.

Examples of the inflammatory disease include arthritis, rheumatoidarthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn'sdisease, and irritable bowel syndrome.

Examples of the autoimmune disease include psoriasis, amyotrophiclateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome,systemic lupus erythematosus, and AIDS.

Examples of the metabolic disease include obesity, metabolic syndrome,dyslipidemia, diabetes, and fatty liver.

Examples of the malignant tumor include breast cancer, ovarian cancer,large bowel cancer (for example, colon cancer), lung cancer (forexample, non-small cell lung cancer), prostate cancer, head and neckcancer (for example, oral squamous cell cancer, head and neck squamouscell cancer, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroidcancer, and acoustic schwannoma), lymphoma (for example, B-cell lymphomaand T-cell lymphoma), uveal malignant melanoma, thymoma, mesothelioma,esophageal cancer, gastric cancer, duodenal cancer, hepatocellularcancer, bile duct cancer, gallbladder cancer, pancreatic cancer, renalcell cancer, renal pelvic and ureteral cancer, bladder cancer, penilecancer, testicular cancer, uterine cancer, vaginal cancer, vulvarcancer, skin cancer (for example, malignant melanoma), malignant bonetumor, soft tissue sarcoma, chondrosarcoma, leukemia (for example, acutemyelogenous leukemia, acute lymphocytic leukemia, chronic myelogenousleukemia, and chronic lymphocytic leukemia), myelodysplastic syndrome,brain tumor or multiple myeloma.

In the present specification, the prevention and/or treatment of amalignant tumor includes, for example, (a) a treatment for reducing theproliferation of cancer cells, (b) a treatment for attenuating symptomsresulting from cancer and improving the quality of life of a cancerpatient, (c) a treatment for reducing the dose of other anticanceragents or cancer therapeutic adjuvants that have already beenadministered, (d) a treatment for suppressing the progression of cancer,(e) a treatment for suppressing the recurrence of cancer, and/or (f) atreatment for prolonging the survival of a cancer patient. In addition,“suppressing the progression of cancer” means to delay the progressionof cancer, stabilize symptoms associated with cancer, and reverse theprogression of symptoms. “Suppressing the recurrence” means to preventcancer recurrence in a patient whose cancer lesion has completely orsubstantially eliminated or removed by cancer treatment or cancersurgical resection.

In the use of the compound of the present disclosure for the purpose ofpreventing and/or treating the above-mentioned diseases, the substancethat acts as an active ingredient, is usually formulated together with apharmaceutically acceptable carrier such as various additives orsolvents, and then administered systemically or topically, orally orparenterally. Here, the pharmaceutically acceptable carrier means asubstance other than the active ingredient, which is generally used forpharmaceutical preparation. The pharmaceutically acceptable carrierpreferably does not exhibit a pharmacological action at the dosage ofthe preparation, is harmless, and does not interfere with thetherapeutic effect of the active ingredient. The pharmaceuticallyacceptable carrier can also be used for the purpose of, for example,enhancing the usefulness of the active ingredient and the preparation,facilitating the formulation, stabilizing the quality, or improving theusability. Specifically, substances described in “JapanesePharmaceutical Excipients Directory” published in 2000 by Yakuji NippoLimited (edited by International Pharmaceutical Excipients CouncilJapan) and the like may be appropriately selected according to thepurpose.

The compound of the present disclosure can be administered to a mammal(preferably human, more preferably a human patient) in apharmaceutically effective amount.

Since the dosage of the compound of the present disclosure depends onage, body weight, symptom, desired therapeutic effect, route ofadministration, period of treatment, and the like, the dosage inevitablyvaries. The compound of the present disclosure is generally administeredorally in the range of 0.1 ng to 1,000 mg per patient peradministration, or parenterally administered or continuouslyadministered intravenously in the range of 0.01 ng to 100 mg per patientper administration.

Needless to say, the dosage varies depending on various conditions asdescribed above. Therefore, a dosage smaller than the above dosage maybe sufficient, or a dosage beyond the above range may be required.

Examples of the dosage form thereof include preparations for oraladministration (for example, tablets, capsules, granules, powders, oralsolutions, syrups, and oral jellies), preparations for oral cavity (forexample, oral tablets, oral sprays, oral semisolids, and oral rinses),preparations for injection (for example, injectables), preparations fordialysis (for example, dialysis agents), preparations for inhalation(for example, inhalants), preparations for ophthalmic application (forexample, eye drops and ophthalmic ointments), preparations for otologicapplication (for example, ear drops), preparations for nasal application(for example, nose drops), preparations for rectum (for example,suppositories, semisolids for rectum, and enemas for rectalapplication), preparations for vagina (for example, vaginal tablets andvaginal suppositories), and preparations for skin (for example, externalsolid agents, external liquid agents, sprays, ointments, creams, gels,and patches).

[Preparation for Oral Administration]

Examples of the preparation for oral administration include tablets,capsules, granules, powders, oral solutions, syrups, and oral jellies.The preparation for oral administration includes rapidly disintegratingpreparations in which the releasability of the active ingredient fromthe preparation is not particularly adjusted; and controlled-releasepreparations such as enteric-coated preparations and sustained-releasepreparations in which the releasability is adjusted according to thepurpose by unique formulation design and formulation method. Theenteric-coated preparation refers to a preparation designed to releasethe active ingredient mainly in the small intestine without releasingthe active ingredient in the stomach, for the purpose of preventing thedegradation of the active ingredient in the stomach or reducing theirritation of the active ingredient to the stomach. The enteric-coatedpreparation can be usually produced by coating with an acid-insolubleenteric-coated base. The sustained-release preparation refers to apreparation in which the release rate, release time, and release site ofthe active ingredient from the preparation are adjusted for the purposeof reducing the number of administrations or attenuating side effects.The sustained-release preparation can be usually produced by using anappropriate sustained-release agent. Among preparations for oraladministration, capsules, granules, tablets, and the like can be coatedwith an appropriate coating agent such as a saccharide, a sugar alcohol,or a polymer compound, for the purpose of, for example, facilitatingingestion or preventing degradation of the active ingredient.

(1) Tablet

The tablet is a solid preparation that is administered orally and has acertain shape. The tablet includes those generally referred to astablets, such as uncoated tablets, film-coated tablets, sugar-coatedtablets, multilayer tablets, and dry-coated tablets, as well as orallyrapidly disintegrating tablets, chewable tablets, effervescent tablets,dispersible tablets, and soluble tablets. In the production of theuncoated tablet, the following method (a), (b), or (c) is usually used:

-   -   (a) Additives such as an excipient, a binder, and a disintegrant        are added to the active ingredient and mixed to prepare a        homogeneous mixture, the mixture is granulated by an appropriate        method using water or a solution containing a binder, then a        lubricant or the like is added to the granulated product and        mixed, and the resulting mixture was compression-molded;    -   (b) Additives such as an excipient, a binder, and a disintegrant        are added to the active ingredient and mixed to prepare a        homogeneous mixture, and the mixture is directly        compression-molded; or the active ingredient, a lubricant, and        the like are added to granules prepared in advance with        additives to prepare a homogeneous mixture, and then the mixture        is compression-molded; and    -   (c) Additives such as an excipient and a binder are added to the        active ingredient and mixed to prepare a homogeneous mixture, a        kneaded product obtained by wetting the mixture with a solvent        is poured into a predetermined mold and molded, and then the        molded product is dried by an appropriate method.

The film-coated tablet can be usually produced by thinly coating anuncoated tablet with an appropriate coating agent such as a polymercompound. The sugar-coated tablet can be usually produced by coating anuncoated tablet with a coating agent containing a saccharide or a sugaralcohol. The multilayer tablet can be produced by forming layers ofpowder particles having different compositions and compression-moldingthe layered powder particles by an appropriate method. The dry-coatedtablet can be produced by covering an inner core tablet with an outerlayer having a composition different from that of the inner core tablet.The tablet can also be an enteric-coated tablet or a sustained-releasetablet by a known appropriate method. The orally rapidly disintegratingtablet, the chewable tablet, the effervescent tablet, the dispersibletablet, and the soluble tablet are those in which unique functions areimparted to the tablets by appropriate selection of additives, and canbe produced according to the above-described methods for producing thetablet. Incidentally, the orally rapidly disintegrating tablet refers toa tablet that can be taken by being rapidly dissolved or disintegratedin the oral cavity; the chewable tablet refers to a tablet that ischewed and taken; the effervescent tablet refers to a tablet thatdissolves or disperses while rapidly foaming in water; the dispersibletablet refers to a tablet that is taken by being dispersed in water; andthe soluble tablet refers to a tablet that is taken by being dissolvedin water. The effervescent tablet can be produced by using anappropriate acidic substance, a carbonate, a bicarbonate, or the like asan additive.

(2) Capsule

The capsule is a preparation in which ingredients are filled in acapsule or encapsulated with a capsule base, and includes hard capsules,soft capsules, and the like. The hard capsule can be produced by addingan additive such as an excipient to the active ingredient and mixingthem to prepare a homogeneous mixture, or forming the mixture intoparticles or a molded product by an appropriate method, and filling, ina capsule, the mixture, the particles, or the molded product as it is orafter each content is slightly molded. The soft capsule can be producedby encapsulating a mixture of the active ingredient and an additive in acertain shape with an appropriate capsule base such as gelatin havingincreased plasticity by adding glycerin, D-sorbitol, or the like. Thecapsule may be an enteric-coated capsule or a sustained-release capsuleprepared by a known appropriate method, and a colorant, a preservative,or the like may be added to the capsule base.

(3) Granule

The granule is a preparation granulated in a granular form, and includeseffervescent granules and the like in addition to those generallyreferred to as granules. In the production of the granule, the followingmethod (a), (b), or (c) is usually used:

-   -   (a) An excipient, a binder, a disintegrant, or other additives        are added to a powdery active ingredient and mixed to prepare a        homogeneous mixture, and then the mixture is granulated by an        appropriate method;    -   (b) An additive such as an excipient is added to the active        ingredient prepared in a granular form in advance, and mixed to        prepare a homogeneous mixture; and    -   (c) An additive such as an excipient is added to the active        ingredient prepared in a granular form in advance and mixed, and        the mixture is then formed into granules by an appropriate        method.

The granule may be coated as necessary, and may be an enteric-coatedgranule or a sustained-release granule prepared by a known appropriatemethod. The effervescent granule can be produced by using an appropriateacidic substance, a carbonate, a bicarbonate, or the like as anadditive. The effervescent granule refers to a granule that dissolves ordisperses while rapidly foaming in water. The granule can also be madeinto a fine granule by adjusting the size of the particle.

(4) Powder

The powder is a powdery preparation, and can be usually produced byadding an excipient or other additives to the active ingredient andmixing them to prepare a homogeneous mixture.

(5) Oral Solution

The oral solution is a liquid or flowable viscous gel preparation, andincludes, in addition to those generally referred to as oral solutions,an elixir, a suspension, an emulsion, a lemonade, and the like. The oralsolution can be usually produced by adding an additive and purifiedwater to the active ingredient, followed by mixing, uniformly dissolvingor emulsifying or suspending, and filtering as necessary. The elixirrefers to a clear liquid oral solution containing sweet and aromaticethanol. The elixir can be usually produced by adding ethanol, purifiedwater, a flavoring agent, and white sugar, other saccharides or asweetener to a solid active ingredient or a leachate thereof, dissolvingcomponents, and preparing a clear liquid by filtration or other methods.The suspension refers to an oral solution in which the active ingredientis finely and homogeneously suspended. The suspension can be usuallyproduced by adding a suspending agent or other additives and purifiedwater or oil to a solid active ingredient, and performing suspension byan appropriate method to homogenize the entire active ingredient. Theemulsion refers to an oral solution in which the active ingredient isfinely and homogeneously emulsified. The emulsion can be usuallyproduced by adding an emulsifier and purified water to a liquid activeingredient, and performing emulsification by an appropriate method tohomogenize the mixture. The lemonade refers to a clear liquid oralsolution having a sweet taste and a sour taste.

(6) Syrup

The syrup is a viscous liquid preparation or solid preparationcontaining a saccharide or sweetener, and includes preparations forsyrup and the like. The syrup can be usually produced by adding theactive ingredient to a solution of white sugar, other saccharides or asweetener, or a single syrup, followed by dissolving, mixing,suspending, or emulsifying, and if necessary, boiling the mixed liquid,followed by hot filtration. The preparation for syrup refers to agranular or powdery preparation that becomes a syrup when water isadded, and may also be referred to as a dry syrup. The preparation forsyrup can be usually produced using a saccharide or a sweetener as anadditive in accordance with the method for producing the granule orpowder.

(7) Oral Jelly

The oral jelly is a formed gel preparation having no fluidity, and canbe usually produced by adding an additive and a polymer gel base to theactive ingredient and mixing them, gelatinizing the mixture by anappropriate method, and forming the resulting gel into a certain shape.

[Preparation for Injection]

(1) Injectable

The injectable is a solution, a suspension or an emulsion, or a solidsterile preparation to be dissolved or suspended when used, which isadministered subcutaneously, intramuscularly, or directly administeredto a body tissue such as blood vessel or an organ. The injectableincludes a lyophilized injectable, a powder injectable, a filledsyringe, a cartridge, an infusion, an embedded injectable, a long actinginjectable, and the like, in addition to those generally referred to asinjectables. In the production of the injectable, the following method(a), or (b) is usually used:

-   -   (a) A homogeneous solution is prepared by dissolving,        suspending, or emulsifying the active ingredient as it is or a        mixture obtained by adding an additive to the active ingredient,        in water for injection, another aqueous solvent, a non-aqueous        solvent or the like. Then, the prepared solution is filled in a        container for injection, and then the container is sealed,        followed by sterilization; and    -   (b) A homogeneous solution is prepared by dissolving,        suspending, or emulsifying the active ingredient as it is or a        mixture obtained by adding an additive to the active ingredient,        in water for injection, another aqueous solvent, a non-aqueous        solvent or the like. Then, the prepared solution is aseptically        filtrated or aseptically prepared, the resulting solution is        filled in a container for injection, and the container is        sealed.

The lyophilized injectable can be usually produced by dissolving theactive ingredient as it is or a mixture of the active ingredient and anadditive such as an excipient, in water for injection, asepticallyfiltering the solution, filling the solution in a container forinjection, and then lyophilizing the solution, or directly filling thesolution in a container after lyophilizing the solution in a dedicatedcontainer. The powder injectable can be usually produced bycrystallizing a powder subjected to aseptic filtration to prepare apowder, and if necessary, adding a sterilized additive to the preparedpowder, and filling the powder in a container for injection. A filledsyringe can be usually produced by preparing a solution, a suspension,or an emulsion with the active ingredient as it is or with the activeingredient and an additive, and then filling the prepared solution,suspension, or emulsion in a glass syringe. The cartridge refers to aninjectable used by inserting a cartridge filled with a drug solutioninto a dedicated syringe. The cartridge filled with the drug solutioncan be usually produced by preparing a solution, a suspension, or anemulsion with the active ingredient as it is or with the activeingredient and an additive, and filling the prepared solution,suspension, or emulsion into the cartridge. The infusion refers to 100mL or more of injectable usually administered intravenously. Theembedded injectable refers to a solid or gel-like injection which isapplied subcutaneously, intramuscularly or the like by using animplantation tool or by surgery, for the purpose of releasing the activeingredient over a long period of time. The embedded injectable can beusually produced by using a biodegradable polymer compound and formingthe compound into a pellet, microsphere, or gel. The long actinginjectable refers to an injectable which is applied intramuscularly orthe like for the purpose of releasing the active ingredient over a longperiod of time. The sustained injectable can be usually produced bydissolving or suspending the active ingredient in a vegetable oil or thelike, or preparing a microsphere suspension containing a biodegradablepolymer compound.

The compound of the present disclosure may also be administered as aconcomitant drug in combination with another drug for:

-   -   1) complementation and/or enhancement of the prophylactic and/or        therapeutic effects of the compound;    -   2) improvement of kinetics and absorption, and reduction in        dosage; and/or    -   3) attenuation of side effects of the compound.

With respect to a combination drug comprising the compound of thepresent invention and other drug, may be administered in the form of ablending drug in which both ingredients are blended in one preparation,or may be administered in the form of separate preparations.Administration in this separate preparations includes simultaneousadministration and administration by time difference. In addition,administration by time difference may be performed by administering thecompound of the present disclosure first and then administering anotherdrug later, or by administering another drug first and thenadministering the compound of the present disclosure later. Theadministration methods of the drugs may be the same or different.

The disease for which the above combination drug has a prophylacticand/or therapeutic effect is not particularly limited as long as it is adisease for which the prophylactic and/or therapeutic effect of thecompound of the present disclosure are complemented and/or enhanced.

Other drugs for complementing and/or enhancing the prophylactic and/ortherapeutic effect of the compound of the present disclosure on paininclude, for example, acetaminophen, non-steroidal anti-inflammatorydrugs, opioid drugs, antidepressant drugs, antiepileptic drugs,N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmicdrugs, steroid drugs, and bisphosphonate drugs.

Examples of the non-steroidal anti-inflammatory drug include aspirinpreparations such as sasapyrine, sodium salicylate, aspirin, andaspirin-dialuminate formulation, diflunisal, indomethacin, suprofen,ufenamate, dimethylisopropyl azulene, bufexamac, felbinac, diclofenac,tolmetin sodium, Clinoril, fenbufen, nabumetone, proglumetacin,indomethacin farnesil, acemetacin, proglumetacin maleate, amfenacsodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen,flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium,tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen,zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid,floctafenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam,ampiroxicam, Napageln ointment, epirizole, tiaramide hydrochloride,tinolidine hydrochloride, emorfazone, sulpyrine, Migrenin, Saridon,Sedes G, Amipylo-N, solbone, a pyrine cold remedy, acetaminophen,phenacetin, dimetotiazine mesylate, meloxicam, celecoxib, rofecoxib,valdecoxib, a simetride blending drug, and a non-pyrine cold remedy.

Examples of the opioid drug include codeine, fentanyl, hydromorphone,levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone,propoxyphene, and tramadol.

Examples of the antidepressant drug include tricyclic antidepressantdrugs (for example, amitriptyline hydrochloride, imipraminehydrochloride, clomipramine hydrochloride, dosulepin hydrochloride,nortriptyline hydrochloride, lofepramine hydrochloride, trimipraminemaleate, and amoxapine), tetracyclic antidepressant drugs (for example,maprotiline hydrochloride, mianserin hydrochloride, and setiptilinemaleate), monoamine oxidase (MAO) inhibitors (safrazine hydrochloride),serotonin and noradrenaline reuptake inhibitors (SNRI) (for example,milnacipran hydrochloride and venlafaxine hydrochloride), selectiveserotonin reuptake inhibitors (SSRI) (for example, fluvoxamine maleate,paroxetine hydrochloride, fluoxetine hydrochloride, and citalopramhydrochloride), and serotonin reuptake inhibitors (for example,trazodone hydrochloride).

Examples of the antiepileptic drug include phenobarbital, pridomine,phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam,carbamazepine, sodium valproate, acetazolamide, and sulthiame.

Examples of the N-methyl-D-aspartate antagonist include ketaminehydrochloride, amantadine hydrochloride, memantine hydrochloride,dextromethorphan, and methadone.

Examples of the muscle relaxant include succinylcholine, suxamethonium,vecuronium bromide, pancuronium bromide, and dantrolene sodium.

Examples of the antiarrhythmic drug include procainamide, disopyramide,cibenzoline, pirmenol, lidocaine, mexiletine, aprindine, pilsicainide,flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone,sotalol, verapamil, diltiazem, and bepridil.

Examples of the steroid drug include, as an external medicine,clobetasol propionate, diflorasone acetate, fluocinonide, mometasonefuroate, betamethasone dipropionate, betamethasone butyrate propionate,betamethasone valerate, difluprednate, budesonide, diflucortolonevalerate, amcinonide, halcinonide, dexamethasone, dexamethasonepropionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclomethasone dipropionate, triamcinoloneacetonide, flumethasone pivalate, alclometasone dipropionate,clobetasone butyrate, prednisolone, beclomethasone dipropionate, andfludroxycortide.

Examples of the internal medicine or injection include cortisoneacetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisonesodium succinate, fludrocortisone acetate, prednisolone, prednisoloneacetate, prednisolone sodium succinate, prednisolone butylacetate,prednisolone sodium phosphate, halopredone acetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,triamcinolone, triamcinolone acetate, triamcinolone acetonide,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,dexamethasone palmitate, paramethasone acetate, and betamethasone.

Examples of the inhalant include beclomethasone dipropionate,fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P,ciclesonide, dexamethasone palomithionate, mometasone furancarbonate,prasterone sulfonate, deflazacort, methylprednisolone suleptanate, andmethylprednisolone sodium succinate.

Examples of the bisphosphonate drug include etidronate, pamidronate,alendronate, risedronate, zoledronate, and minodronate.

Any two or more of the other drugs may be administered in combination.

In addition, other drugs that complement and/or enhance the prophylacticand/or therapeutic effect of the compound of the present disclosureinclude not only those that have been found to date but also those thatwill be found in the future based on the mechanism described above.

Unless defined otherwise, all technical, scientific terms, andabbreviations used herein have the same meaning as commonly understoodby one of ordinary skill in the art to which this invention belongs.

In addition, in the present specification, all contents of all patentdocuments and non-patent documents or references explicitly cited may becited herein as part of the present specification.

In one aspect, the present disclosure provides the followingembodiments.

[1] A compound represented by general formula (I-A) or apharmaceutically acceptable salt thereof:

-   -   wherein    -   X¹ and X² each independently represent (1) CH, (2) CR^(X),        or (3) N, provided that at least one of X¹ and X² represents N,    -   R¹ represents a halogen atom,    -   R^(X) represents (1) a halogen atom, (2) a C1-6 alkyl group, (3)        a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6        alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   R² represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   when m is 2 or more, a plurality of R²s may be the same or        different,    -   R³ represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a        C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5)        —(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) —(C1-6        haloalkylene)-(3- to 10-membered cyclic group), wherein one to        two carbon atoms in the C1-6 alkyl group, the C1-6 haloalkyl        group, the C1-6 alkylene, and the C1-6 haloalkylene may be        replaced with an oxygen atom or an optionally oxidized sulfur        atom,    -   the 3- to 10-membered cyclic group in R³ may be substituted with        one to five R³⁰¹s,    -   R³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C1-4 haloalkyl group, (5) a C1-4        haloalkoxy group, (6) COOR³⁰², (7) CONR³⁰³R³⁰⁴, (8) a C3-6        cycloalkyl group, (9) a hydroxyl group, (10) a nitro group, (11)        a cyano group, (12) —NR³⁰⁵R³⁰⁶, (13) —SR³⁰⁷, (14) —SOR³⁰⁸, (15)        —SO₂R³⁰⁹, or (16) an oxo group,    -   when two or more R³⁰¹s are substituted, a plurality of R³⁰¹s may        be the same or different,    -   R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, or R³⁰⁹ each        independently represent (1) a hydrogen atom or (2) a C1-4 alkyl        group,    -   when R² represents (2) to (9) in R², and R³ represents a C1-6        alkyl group, R² and R³, together with an atom to which R² and R³        are bonded, may form a 5- to 6-membered cyclic group,    -   R⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy        group,    -   when n is 2 or more, a plurality of R⁴s may be the same or        different,    -   when two R⁴s present on the same carbon atom represent a C1-6        alkyl group, the two R⁴s, together with a carbon atom to which        the two R⁴s are bonded, may form a C3-6 cycloalkyl group,    -   ring 1 represents a 3- to 15-membered cyclic group,    -   R^(5-A) represents (1) a halogen atom, (2) a C1-6 alkyl        group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a        C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6        alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6        acyl group, (10) a 3- to 6-membered cyclic group, (11)        -L^(R5)-(3- to 6-membered cyclic group), (12) a hydroxyl        group, (13) a nitro group, (14) a cyano group, (15) an oxo        group, (16) —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵,        or (19) —SO₂NR⁵⁰⁶R⁵⁰⁷, wherein one to two carbon atoms in the        C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl        group, the C1-6 alkoxy group, the C1-6 alkylthio group, the C1-6        alkylsulfinyl group, the C1-6 alkylsulfonyl group, and the C2-6        acyl group may be replaced with an oxygen atom or an optionally        oxidized sulfur atom,    -   when p is 2 or more, a plurality of R^(5-A)s may be the same or        different,    -   the groups (2) to (11) in R^(5-A) may be substituted with one to        nine R⁵⁰⁸s,    -   R⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6        cycloalkyl group, (6) a hydroxyl group, or (7) —NR⁵⁰⁹R⁵¹⁰,    -   when two or more R⁵⁰⁸s are substituted, a plurality of R⁵⁰⁸s may        be the same or different,    -   L^(R5) represents (1) —O—, (2) —(C1-4 alkylene)-, (3) —O—(C1-4        alkylene)-, (4) —(C1-4 alkylene)-O—, (5) —NR⁵¹¹—, or (6)        —SO₀₋₂—,    -   R⁵⁰¹, R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, R⁵⁰⁹, R⁵¹⁰, or R⁵¹¹        each independently represent (1) a hydrogen atom, (2) a C1-6        alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl        group,    -   m represents an integer of 0 to 2,    -   n represents an integer of 0 to 5, and    -   p represents an integer of 0 to 5.

[2] A compound represented by general formula (I) or a pharmaceuticallyacceptable salt thereof:

-   -   wherein    -   X¹ and X² each independently represent (1) CH, (2) CR^(X),        or (3) N, provided that at least one of X¹ and X² represents N,    -   R¹ represents a halogen atom,    -   R^(X) represents (1) a halogen atom, (2) a C1-6 alkyl group, (3)        a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6        alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   R² represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy        group, or (10) a cyano group,    -   when m is 2 or more, a plurality of R²s may be the same or        different,    -   R³ represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a        C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5)        —(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) —(C1-6        haloalkylene)-(3- to 10-membered cyclic group), wherein one to        two carbon atoms in the C1-6 alkyl group, the C1-6 haloalkyl        group, the C1-6 alkylene, and the C1-6 haloalkylene may be        replaced with an oxygen atom or an optionally oxidized sulfur        atom,    -   the 3- to 10-membered cyclic group in R³ may be substituted with        one to five R³⁰¹s,    -   R³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C1-4 haloalkyl group, (5) a C1-4        haloalkoxy group, (6) COOR³⁰², (7) CONR³⁰³R³⁰⁴, (8) a C3-6        cycloalkyl group, (9) a hydroxyl group, (10) a nitro group, (11)        a cyano group, (12) —NR³⁰⁵R³⁰⁶, (13) —SR³⁰⁷, (14) —SOR³⁰⁸, (15)        —SO₂R³⁰⁹, or (16) an oxo group,    -   when two or more R³⁰¹s are substituted, a plurality of R³⁰¹s may        be the same or different,    -   R³⁰², R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, or R³⁰⁹ each        independently represent (1) a hydrogen atom or (2) a C1-4 alkyl        group,    -   when R² represents (2) to (9) in R², and R³ represents a C1-6        alkyl group, R² and R³, together with an atom to which R² and R³        are bonded, may form a 5- to 6-membered cyclic group,    -   R⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl        group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy        group,    -   when n is 2 or more, a plurality of R⁴s may be the same or        different,    -   when two R⁴s present on the same carbon atom represent a C1-6        alkyl group, the two R⁴s, together with a carbon atom to which        the two R⁴s are bonded, may form a C3-6 cycloalkyl group,    -   ring 1 represents a 3- to 15-membered cyclic group,    -   R⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a        C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy        group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl        group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl        group, (10) a 3- to 6-membered cyclic group, (11) -L^(R5)-(3- to        6-membered cyclic group), (12) a hydroxyl group, (13) a nitro        group, (14) a cyano group, (15) an oxo group, (16)        —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵, or (19)        —SO₂NR⁵⁰⁶R⁵⁰⁷,    -   when p is two or more, a plurality of R⁵s may be the same or        different,    -   the groups (2) to (11) in R⁵ may be substituted with one to nine        R⁵⁰⁸s,    -   R⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3)        a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6        cycloalkyl group, (6) a hydroxyl group, or (7) —NR⁵⁰⁹R⁵¹⁰,    -   when two or more R⁵⁰⁸s are substituted, a plurality of R⁵⁰⁸s may        be the same or different,    -   L^(R5) represents (1) —O—, (2) —(C1-4 alkylene)-, (3) —O—(C1-4        alkylene)-, (4) —(C1-4 alkylene)-O—, (5) —NR⁵¹¹—, or (6)        —SO₀₋₂—,    -   R⁵⁰¹, R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, R⁵⁰⁹, R⁵¹⁰, or R⁵¹¹        each independently represent (1) a hydrogen atom, (2) a C1-6        alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl        group,    -   m represents an integer of 0 to 2,    -   n represents an integer of 0 to 5, and    -   p represents an integer of 0 to 5.

[3] The compound or the pharmaceutically acceptable salt thereofaccording to the above [1] or [2], wherein ring 1 is a 3- to 10-memberedcyclic group, or

-   -   wherein the * mark represents a bonding position with a carbonyl        group.

[4] The compound or the pharmaceutically acceptable salt thereofaccording to the above [1] or [3], wherein ring 1 represents a ringstructure selected from the group consisting of the following ringstructures;

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-A).

[5] The compound or the pharmaceutically acceptable salt thereofaccording to the above [2] or [3], wherein ring 1 represents a ringstructure selected from the group consisting of the following ringstructures;

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R⁵.

[6] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [5], wherein ring 1 representsa ring structure selected from the group consisting of the followingring structures

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-A) or R⁵.

[7] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [6], wherein R^(5-A) or R⁵ is(1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4)a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a 3- to6-membered cyclic group, (7) an oxo group, (8) —NR⁵⁰¹R⁵⁰², or (9)—COOR⁵⁰³.

[8] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [7], wherein R^(5-A) or R⁵ is(1) a C1-6 alkyl group, (2) a C1-6 alkoxy group, (3) a C1-6 haloalkylgroup, (4) a C1-6 haloalkoxy group, (5) a cyclopropyl group, (6) a furanring, (7) an N-methylpyrazole ring, (8) an oxo group, (9) adimethylamino group, or (10) —COOCH₃.

[9] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [8], wherein R³ is (1) ahydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a3- to 10-membered cyclic group, or (5) —CH₂-(3- to 10-membered cyclicgroup).

[10] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [9], wherein R³ represents (1)a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4)a cyclopropyl group, or (5) —CH₂-Q, and

-   -   Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

[11] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [10], wherein X¹ and X² areboth N.

[12] The compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [11], wherein the compoundrepresented by general formula (I-A) or general formula (I) is acompound represented by general formula (I-1):

-   -   wherein R^(3-a) represents (1) a hydrogen atom, (2) a C1-6 alkyl        group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group,        or (5) —CH₂-Q,    -   ring 1-a represents a ring structure selected from the group        consisting of the following ring structures;

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-a),    -   R^(5-a) represents (1) a C1-6 alkyl group, (2) a C1-6 alkoxy        group, (3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy        group, (5) a cyclopropyl group, (6) a furan ring, (7) an        N-methylpyrazole ring, (8) an oxo group, (9) a dimethylamino        group, or (10) —COOCH₃, and    -   other symbols represent the same meaning as the symbols        described in the above [1], [2], or [10].

[13] The compound or the pharmaceutically acceptable salt thereofaccording to the above [12], wherein ring 1-a represents a ringstructure selected from the group consisting of the following ringstructures;

-   -   wherein the * mark represents a bonding position with a carbonyl        group, and a hydrogen atom represented by NH may be replaced        with R^(5-a).

[14] The compound or the pharmaceutically acceptable salt thereofaccording to the above [1] or [2], wherein the compound represented bygeneral formula (I-A) or general formula (I) is a compound selected fromthe group consisting of:

-   (1)    {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone,-   (2)    {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone,-   (3)    [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,-   (4)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,-   (5)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,-   (6)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,-   (7)    [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,-   (8)    rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino)-4-pyridazinecarbonitrile,-   (9)    {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,    and-   (10)    [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl],(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone.

[15] The compound or the pharmaceutically acceptable salt thereofaccording to the above [1] or [2], wherein the compound represented bygeneral formula (I-A) or general formula (I) is a compound selected fromthe group consisting of:

-   (1)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,-   (2)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone,-   (3)    [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone,    and-   (4)    [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone.

[16] A pharmaceutical composition containing the compound or thepharmaceutically acceptable salt thereof according to any one of theabove [1] to [15] as an active ingredient, and a pharmaceuticallyacceptable carrier.

[17] The pharmaceutical composition according to the above [16], whichis an ABHD6 inhibitor.

[18] The pharmaceutical composition according to the above [16] or [17],which is an agent for treating and/or preventing a disease associatedwith ABHD6.

[19] The pharmaceutical composition according to the above [18], whereinthe disease associated with ABHD6 is pain, a neurological disease, aninflammatory disease, an autoimmune disease, a metabolic disease, or amalignant tumor.

[20] The pharmaceutical composition according to the above [18] or [19],wherein the disease associated with ABHD6 is pain, and the pain is painassociated with osteoarthritis, cancer pain, pain associated withchemotherapy, chronic low back pain, low back pain associated withosteoporosis, fracture pain, pain associated with rheumatoid arthritis,neuropathic pain, post-herpetic pain, pain associated with diabeticneuropathy, pain associated with fibromyalgia, pain associated withpancreatitis, pain associated with interstitial cystitis or bladder painsyndrome, pain associated with endometriosis, pain associated withirritable bowel syndrome, migraine, or pain associated with pulpitis.

[21] The pharmaceutical composition according to any one of the above[16] to [20], wherein the pharmaceutical composition is administered incombination with one or more selected from the group consisting ofacetaminophen, non-steroidal anti-inflammatory drugs, opioid drugs,antidepressant drugs, antiepileptic drugs, N-methyl-D-aspartateantagonists, muscle relaxants, antiarrhythmic drugs, steroid drugs, andbisphosphonate drugs.

[22] An agent for treating and/or preventing a disease associated withABHD6, containing the compound or the pharmaceutically acceptable saltthereof according to any one of the above [1] to [15].

[23] A method for preventing and/or treating a disease associated withABHD6, the method including administering the compound or thepharmaceutically acceptable salt thereof according to any one of theabove [1] to [15], or the pharmaceutical composition according to theabove [16] or [17] to a patient in need of prevention and/or treatmentof a disease associated with ABHD6.

[24] A compound or a pharmaceutically acceptable salt thereof accordingto any one of the above [1] to [15], for use in preventing and/ortreating a disease associated with ABHD6.

[25] Use of the compound or the pharmaceutically acceptable salt thereofaccording to any one of the above [1] to [15], in the manufacture of anagent for preventing and/or treating a disease associated with ABHD6.

SYNTHESIS EXAMPLES

The solvent in parentheses shown in the description of the separation bychromatography and TLC indicates an eluting solvent or developingsolvent used therefor, and the ratio represents the volume ratio.

The solvent in parentheses shown in the description of NMR indicates thesolvent used for the measurement.

The compound names used in the present specification are named using acomputer program ACD/Name (registered trademark), which generallyperforms naming according to the IUPAC nomenclature, or using a ChemdrawUltra (Version 12.0, manufactured by Cambridge Soft), or according tothe IUPAC nomenclature.

LC-MS/ELSD was performed under the following TFA conditions or formicacid conditions.

TFA conditions;

Column: YMC Triart C₁₈ (particle size: 1.9×10⁻⁶ m; Column length: 30×2.0mm I.D.); Flow rate: 1.0 mL/min; Column temperature: 30° C.; Mobilephase (A): 0.1% aqueous trifluoroacetic acid solution; Mobile phase (B):0.1% trifluoroacetic acid-acetonitrile solution; Gradient (ratio ofmobile phase (A):mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5; [1.2min] 5:95; [1.6 min] 5:95; Detector: UV (PDA), ELSD, MS.

Formic acid conditions;

Column: YMC Triart C₁₈ (particle size: 1.9×10⁻⁶ m; Column length: 30×2.0mm I.D.); Flow rate: 1.0 mL/min; Column temperature: 30° C.; Mobilephase (A): 0.1% aqueous formic acid solution; Mobile phase (B): 0.1%formic acid-acetonitrile solution; Gradient (ratio of mobile phase(A):mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95;[1.6 min] 5:95; Detector: UV (PDA), ELSD, MS.

The HPLC retention time indicates the retention time under theconditions described in the LC-MS/ELSD if not stated otherwise. Thedescription in parentheses shown in the HPLC retention time indicatesthe measurement conditions.

Reference Example 1: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one

To a dichloromethane solution (600 mL) ofN-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (CAS No.:93102-05-7, 50 g), were added 2-cyclopentenone (CAS No.: 930-30-3, 17 g)and trifluoroacetic acid (CAS No.: 76-05-1, 240 mg), and the mixture wasstirred at room temperature for 16 hours. Triethylamine (430 mg) wasadded to the reaction solution, and the mixture was concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (30 g).

HPLC retention time (min): 0.65 (TFA);

MS (ESI, Pos.): 226 (M+H)⁺.

Reference Example 2: (R)—N-((3aS, 6aR,E)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(1H)-ylidene)-2-methylpropane-2-sulfinamide

Titanium(IV) ethoxide (CAS No.: 3037-36-3, 46.6 g) and(R)-(+)-2-methyl-2-propanesulfinamide (CAS No.: 196929-78-9, 11.8 g)were added to a solution of the compound (20 g) prepared in ReferenceExample 1 in THF (300 mL), and the mixture was stirred at 60° C. for 15hours. The reaction solution was slowly poured into a saturated aqueoussodium bicarbonate solution and dichloromethane, and filtered. Themixture was washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography to obtain the titlecompound (12.4 g).

HPLC retention time (min): 0.80 (TFA);

MS (ESI, Pos.): 319 (M+H)⁺.

Reference Example 3: (3aS,6aR)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one

To a solution of the compound (20 g) prepared in Reference Example 2 inTHF (60 mL), was added 2 N hydrochloric acid (60 mL), and the mixturewas stirred at room temperature for 1 hour. The reaction solution wasneutralized with 2 N sodium hydroxide, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained title compound was used for the next reactionwithout purification.

Reference Example 4: 2-Methyl-2-propanyl (3aS,6aR)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Di-tert-butyl dicarbonate (CAS No.: 24424-99-5, 9.4 g) and 20% palladiumhydroxide (CAS No.: 12135-22-7, 700 mg) were added to a solution of thecompound prepared in Reference Example 3 in THE (60 mL), and the mixturewas stirred under a hydrogen atmosphere at room temperature for 15hours. The reaction solution was filtered and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (7.0 g).

¹H-NMR (CD₃OD): δ 3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35,2.21-2.12, 1.87 1.45.

Reference Example 5: 2-Methyl-2-propanyl (3aS, 4S,6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A 1 M lithium tri-sec-butylborohydride THF solution (CAS No.:38721-52-7, 49 mL) was added to a solution of the compound (7.3 g)prepared in Reference Example 4 in THE (200 mL) at −78° C., and themixture was stirred at −78° C. for 1 hour. A 35% aqueous hydrogenperoxide solution was slowly added to the reaction solution at 0° C.until foaming stopped, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (6.5 g).

¹H-NMR (CDCl₃): δ 4.30-4.25, 3.63-3.50, 3.38-3.30, 3.17-3.15, 2.67,1.90-1.73, 1.73-1.54, 1.47.

Reference Example 6: 2-Methyl-2-propanyl (3aS, 4S,6aR)-4-{[(4-methylphenyl)sulfonyl]oxy}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Triethylamine (12 mL), p-toluenesulfonyl chloride (CAS No.: 98-59-9, 8.2g), and trimethylamine hydrochloride (CAS No.: 75-50-3, 820 mg) wereadded to a solution of the compound (6.5 g) prepared in ReferenceExample 5 in dichloromethane (100 mL), and the mixture was stirred atroom temperature for 6 hours. A saturated aqueous sodium bicarbonatesolution was added to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (9.3 g).

HPLC retention time (min): 1.2 (TFA);

MS (ESI, Pos.): 382 (M+H)⁺.

Reference Example 7: 2-Methyl-2-propanyl(3aS,4R,6aR)-4-azidohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Sodium azide (CAS No.: 26628-22-8, 3.2 g) was added to a solution of thecompound (9.3 g) prepared in Reference Example 6 in dimethyl sulfoxide(72 mL), and the mixture was stirred at 60° C. for 6 hours. Water wasadded to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, concentrated under reducedpressure, and used for the next reaction without purification.

Reference Example 8: 2-Methyl-2-propanyl(3aS,4R,6aR)-4-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of the compound (6.5 g) prepared in Reference Example 7 inethanol (240 mL), was added 20% palladium hydroxide (930 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for15 hours. The reaction solution was filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (4.5 g).

HPLC retention time (min): 0.77 (TFA);

MS (ESI, Pos.): 227 (M+H)⁺.

Reference Example 9: 2-Methyl-2-propanyl(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

N,N-diisopropylethylamine (hereinafter, DIPEA) (6.9 mL) and3,6-dichloropyridazine (CAS No.: 141-30-0, 1.5 g) were added to asolution of the compound (1.5 g) prepared in Reference Example 8 inN,N-dimethylacetamide (hereinafter, DMA) (25 mL), and the mixture wasstirred at 160° C. for 1 hour. Water was added to the reaction solution,followed by extraction with dichloromethane. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (1.5g).

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 339 (M+H)⁺.

Reference Example 10:(3aS,4R,6aR)—N-(6-Chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-aminedihydrochloride

To the compound (1.2 g) prepared in Reference Example 9, was added 4 Nhydrochloric acid (1,4 dioxane solution, 12 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to obtain the title compound (1.0g).

HPLC retention time (min): 0.59 (formic acid);

MS (ESI, Pos.): 239 (M+H)⁺.

Reference Example 10-1:rel-(3aS,4R,6aR)—N-(6-Chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-aminedihydrochloride racemic mixture

The same procedures as in Reference Example 4→Reference Example5→Reference Example 6→Reference Example 7→Reference Example 8→ReferenceExample 9→Reference Example 10 were carried out using the compoundprepared in Reference Example 1 in place of the compound prepared inReference Example 3 to obtain the title compound.

Example 1:{(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone

DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CASNo.: 189330-23-2, 19 mg), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (hereinafter, HATU) (CAS No.: 148893-10-1, 38 mg)were added to a solution of the compound (30 mg) prepared in ReferenceExample 10 in DMA (0.5 mL), and the mixture was stirred at roomtemperature for 3 hours. Water was added to the reaction solution,followed by extraction with dichloromethane. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (32mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 399 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.43, 7.18, 6.83, 6.63, 4.78-4.52, 4.12, 3.88, 3.67,3.49, 2.99-2.80, 2.79-2.61, 2.36, 2.13, 1.69-1.57.

Examples 1-1 to 1-6

The same procedure as in Example 1 was carried out using a correspondingcarboxylic acid compound in place of5-(difluoromethyl)thiophene-2-carboxylic acid, and using the compoundprepared in Reference Example 10 or the compound prepared in ReferenceExample 10-1 in place of the compound prepared in Reference Example 10to obtain each of the title compounds.

Example 1-1:rel-1,3-Benzothiazol-2-yl{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}methanoneracemic mixture

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 400 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.23-8.14, 7.64-7.55, 7.42-7.30, 6.92, 4.44-4.27,4.14-4.07, 4.24-4.03, 3.93-3.81, 3.78-3.66, 3.55-3.47, 3.35-3.24,3.23-3.05, 3.00-2.70, 2.61-2.54, 2.26-2.16, 2.13-1.97, 1.66-1.49.

Example 1-2:{(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone

HPLC retention time (min): 0.85 (TFA);

MS (ESI, Pos.): 363 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.35-7.28, 7.16, 6.76-6.71, 6.65, 4.96, 4.14-3.96,3.96-3.86, 3.82, 3.65, 2.88, 2.79-2.62, 2.50, 2.41-2.27, 2.18-2.04,1.72-1.54.

Example 1-3:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)methanone

HPLC retention time (min): 0.74 (formic acid);

MS (ESI, Pos.): 400 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.46-9.25, 8.63-8.43, 8.40-8.30, 8.29-8.14,7.43-7.30, 6.97-6.83, 4.20-4.00, 3.99-3.65, 3.15-3.04, 3.04-2.79,2.77-2.57, 2.27-2.15, 2.14-1.98, 1.70-1.58, 1.58-1.48.

Example 1-4:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 405 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.22-7.13, 6.66, 5.04, 4.76-4.65, 4.12, 3.98, 3.86,3.64, 2.89, 2.70, 2.39-2.28, 2.17-2.07, 1.69-1.55.

Example 1-5:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(2-furyl)phenyl]methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 409 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.14-8.07, 8.07-7.93, 7.73-7.47, 7.43-7.22,6.98-6.88, 6.88-6.78, 4.11-3.99, 3.99-3.88, 3.76-3.65, 3.10, 2.86-2.70,2.21-2.09, 2.09-1.98, 1.98-1.84, 1.65-1.43, 1.43-1.29.

Example 1-6:1-Benzofuran-2-yl[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 383 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.79-7.74, 7.71-7.65, 7.57-7.49, 7.49-7.43,7.41-7.32, 7.31-7.25, 6.96-6.84, 4.14-4.01, 3.83-3.72, 3.34-3.25,2.97-2.76, 2.73-2.66, 2.64-2.53, 2.25-2.15, 2.10-1.98, 1.65-1.57,1.56-1.46.

Reference Example 11: 2-Methyl-2-propanyl(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

DIPEA (18 mL) and 3,6-dibromopyridazine (CAS No.: 17973-86-3, 6.3 g)were added to a solution of the compound (4.0 g) prepared in ReferenceExample 8 in DMA (25 mL), and the mixture was stirred at 160° C. for 15hours. Water was added to the reaction solution, followed by extractionwith dichloromethane. The organic layer was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (4.0 g).

HPLC retention time (min): 0.91 (formic acid);

MS (ESI, Pos.): 383 (M+H)⁺.

Reference Example 12:(3aS,4R,6aR)—N-(6-Bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-aminedihydrochloride

To the compound (4.0 g) prepared in Reference Example 11, was added 4 Nhydrochloric acid (1,4 dioxane solution, 12 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to obtain the title compound (3.7g).

HPLC retention time (min): 0.59 (formic acid);

MS (ESI, Pos.): 283 (M+H)⁺.

Reference Example 12-1:rel-(3aS,4R,6aR)—N-(6-Bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-aminedihydrochloride racemic mixture

The same procedures as in Reference Example 4→Reference Example5→Reference Example 6→Reference Example 7→Reference Example 8→ReferenceExample 11→Reference Example 12 were carried out using the compoundprepared in Reference Example 1 in place of the compound prepared inReference Example 3 to obtain the title compound.

Example 2:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

DIPEA (2.9 mL), 5-methyl-2-thiophenecarboxylic acid (CAS No.: 1918-79-2,6.6 g), and HATU (3.8 g) were added to a solution of the compound (3.0g) prepared in Reference Example 12 in DMA (20 mL), and the mixture wasstirred at room temperature for 3 hours. Water was added to the reactionsolution, followed by extraction with dichloromethane. The organic layerwas washed with saturated saline, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (1.8 g).

HPLC retention time (min): 0.87 (TFA);

MS (ESI, Pos.): 407 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.33-7.27, 6.75-6.72, 6.54, 5.00, 4.15-3.99,3.98-3.78, 3.66, 2.88, 2.68, 2.50, 2.39-2.29, 2.14-2.03, 1.68-1.59.

Examples 2-1 to 2-14

The same procedure as in Example 2 was carried out using a correspondingcarboxylic acid compound in place of 5-methyl-2-thiophenecarboxylic acidto obtain each of the title compounds.

Example 2-1:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

HPLC retention time (min): 0.93 (TFA);

MS (ESI, Pos.): 451 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.32-7.27, 7.17, 6.54, 4.77-4.63, 4.10, 4.04-3.93,3.87, 3.65, 2.89, 2.69, 2.40-2.29, 2.17-2.07, 1.68-1.57.

Example 2-2:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 443 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.63-7.56, 7.50-7.47, 7.46-7.43, 7.34-7.27, 7.32,6.86-6.73, 4.11-3.87, 3.87-3.70, 3.71-3.54, 2.96-2.72, 2.71-2.56,2.23-2.11, 2.09-1.95, 1.59, 1.51.

Example 2-3:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-1,3-thiazol-2-yl)methanone

HPLC retention time (min): 0.96 (formic acid);

MS (ESI, Pos.): 408 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.77-7.68, 7.50-7.41, 7.41-7.28, 6.87-6.77,4.29-3.93, 3.84-3.62, 3.18-3.04, 2.97-2.60, 2.24-2.11, 2.11-1.95,1.66-1.54, 1.54-1.43.

Example 2-4:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)-methanone

HPLC retention time (min): 0.75 (formic acid);

MS (ESI, Pos.): 444 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.42-9.26, 8.60, 8.44-8.31, 8.31-8.17, 7.52-7.42,7.42-7.31, 6.88-6.74, 4.17-4.00, 3.89-3.67, 3.14-3.06, 2.87, 2.28-2.14,2.13-1.97, 1.70-1.45.

Example 2-5:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2-yl)methanone

HPLC retention time (min): 0.84 (TFA);

MS (ESI, Pos.): 452 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.31-7.27, 6.54, 4.85-4.78, 4.73, 4.34-4.27, 4.21,4.15-3.97, 3.95-3.84, 3.78, 3.65, 2.97, 2.90-2.71, 2.69-2.59, 2.39-2.28,2.18-2.01, 1.69-1.61.

Example 2-6:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(dimethylamino)-1,3-thiazol-5-yl]methanone

HPLC retention time (min): 0.74 (TFA);

MS (ESI, Pos.): 438 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.57, 7.26, 6.55, 4.92, 4.15-4.02, 3.98-3.89, 3.87,3.78, 3.61, 3.15, 2.89, 2.69, 2.39-2.29, 2.17-2.07, 1.62-1.55.

Example 2-7:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5,5-dioxide-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.46, 7.33, 6.82, 4.39, 4.11-3.99, 3.97-3.83,3.81-3.65, 3.18-3.05, 2.99-2.72, 2.70-2.58, 2.24-2.09, 2.09-1.96, 1.58,1.49.

Example 2-8:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 465 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.46, 7.41-7.31, 6.86-6.77, 4.11-4.02, 4.02-3.86,3.71, 3.69-3.58, 3.46, 3.15-3.05, 3.04-2.96, 2.94-2.88, 2.88-2.71,2.25-2.12, 2.10-1.94, 1.68-1.54, 1.54-1.39.

Example 2-9:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1-methyl-1H-thieno[2,3c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.90 (formic acid);

MS (ESI, Pos.): 447 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.85, 7.69-7.57, 7.52-7.43, 7.43-7.28, 6.89-6.70,4.12-4.00, 3.96, 3.92-3.67, 3.15-3.05, 2.96-2.75, 2.75-2.57, 2.26-2.11,2.09-1.94, 1.66-1.55, 1.55-1.44.

Example 2-10:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(dimethylamino)thieno[2,3-d][1,3]thiazol-5-yl]methanone

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 493 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.79, 7.44, 7.25, 6.79, 4.16-3.94, 3.86, 3.74, 3.56,3.44-3.36, 3.31-3.23, 3.13, 2.87, 2.61, 2.19, 2.07-1.98, 1.63-1.47.

Example 2-11:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](3-methyl-3H-thieno[2,3-d][1,2,3]triazol-5-yl)methanone

HPLC retention time (min): 0.87 (formic acid);

MS (ESI, Pos.): 448 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.91, 7.46, 7.44-7.36, 6.84, 4.24, 4.14-3.98,3.95-3.61, 3.00-2.79, 2.77-2.59, 2.27-2.16, 2.11-1.98, 1.65-1.57,1.57-1.50.

Example 2-12:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methoxy-2-furyl)methanone

HPLC retention time (min): 0.80 (TFA);

MS (ESI, Pos.): 407 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.31-7.27, 7.05, 6.54, 5.31, 4.81-4.66, 4.12, 3.92,3.94-3.77, 3.76-3.58, 2.95-2.76, 2.72-2.52, 2.34, 2.05, 1.66-1.56.

Example 2-13:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.93 (formic acid);

MS (ESI, Pos.): 461 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.62, 7.51-7.44, 7.45-7.36, 6.88-6.79, 4.13-4.04,3.85, 4.01-3.66, 3.36-3.24, 2.95-2.80, 2.71-2.58, 2.37, 2.26-2.15,2.11-2.00, 1.64-1.57, 1.56-1.48.

Example 2-14:Bicyclo[2.2.2]oct-2-yl[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 419 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.51-7.39, 7.38-7.25, 6.85-6.74, 4.07-3.85,3.73-3.51, 3.29-3.16, 2.87-2.59, 2.18-1.82, 1.72-1.14.

Reference Example 13: Methyl5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-4-nitro-2-thiophenecarboxylate

DIPEA (0.083 mL) and tripotassium phosphate (CAS No.: 7778-53-2, 1730mg), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate(CAS No.: 1009307-13-4, 300 mg), andbis(triphenylphosphine)palladium(II) chloride (CAS No.: 13965-03-2, 63mg) were added to a solution of methyl5-bromo-4-nitrothiophene-2-carboxylate (CAS No.: 38239-32-6, 120 mg) in1,2-dimethoxyethane (3 mL), and the mixture was stirred at 55° C. for 3hours. Water was added to the reaction solution, followed by extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (97 mg).

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 286 (M+H)⁺.

Reference Example 14: Methyl4-amino-5-(3-ethoxy-3-oxopropyl)-2-thiophenecarboxylate

To a solution of the compound (50 mg) prepared in Reference Example 13in methanol (2 mL), was added 20% palladium hydroxide (100 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for1 hour. The reaction solution was filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (30 mg).

HPLC retention time (min): 0.80 (formic acid);

MS (ESI, Pos.): 258 (M+H)⁺.

Reference Example 15: Methyl5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate

To a solution of the compound (20 mg) prepared in Reference Example 14in methanol (1 mL), was added p-toluenesulfonic acid monohydrate (CASNo.: 6192-52-5, 1.5 mg), and the mixture was stirred at 60° C. for 15hours. Saturated sodium bicarbonate water was added to the reactionsolution, followed by extraction with ethyl acetate. The organic layerwas washed with saturated saline, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (5 mg).

HPLC retention time (min): 0.81 (formic acid);

MS (ESI, Pos.): 212 (M+H)⁺.

Reference Example 16: Methyl4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate

Sodium hydride (CAS No.: 7646-69-7, 2.9 mg) and iodomethane (CAS No.:74-88-4, 22 mg) were added to a solution of the compound (5 mg) preparedin Reference Example 15 in DMF (0.25 mL), and the mixture was stirred atroom temperature for 3 hours. Then, 2 N hydrochloric acid was added tothe reaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (7 mg).

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 225 (M+H)⁺.

Reference Example 17:4-Methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (7 mg) prepared in Reference Example 16 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, and theprecipitate was collected by filtration to obtain the title compound(5.0 mg).

Reference Example 18: 5-Chloro-3,4-dihydro-2H-pyran-6-carbaldehyde

DMF (0.70 mL) was added to a solution of phosphoryl chloride (CAS No.:10025-87-3, 1,400 mg) in dichloromethane (5 mL) at 0° C., and themixture was stirred at 0° C. for 1 hour. Dihydro-2H-pyran-3(4H)-one (CASNo.: 23462-75-1, 900 mg) was added to the mixed solution, and themixture was stirred at room temperature for 2 hours. A saturated aqueoussodium bicarbonate solution was added to the reaction solution, followedby extraction with dichloromethane. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 19: Methyl[(6-formyl-3,4-dihydro-2H-pyran-5-yl)thio]acetate

Triethylamine (2.5 mL) and methyl thioglycolate (CAS No.: 2365-48-2,1,100 mg) were added to a solution of the compound prepared in ReferenceExample 18 in dichloroethane (20 mL), and the mixture was stirred at 70°C. for 15 hours. The reaction solution was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography to obtain the title compound (300 mg).

Reference Example 20: Methyl6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate

To a solution of the compound prepared in Reference Example 19 inmethanol (10 mL), was added 28% sodium methoxide (CAS No.: 124-41-4,0.85 mL), and the mixture was stirred at 70° C. for 1 hour. The reactionsolution was concentrated under reduced pressure, and 2 N hydrochloricacid was added thereto, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (220 mg).

Reference Example 21: 6,7-Dihydro-5H-thieno[3,2-b]pyran-2-carboxylicacid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 20 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 449 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.55-7.43, 7.10, 6.89-6.60, 4.67-4.62, 4.17-4.07,4.05-3.87, 3.73, 3.67, 3.42-3.40, 3.37-3.33, 3.30, 3.22-3.04, 2.79-2.70,2.58-2.53, 2.17, 2.09-1.85, 1.71-1.37.

Reference Example 22: Dimethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate

Triethylamine (0.11 mL) and methyl chloroformate (CAS No.: 79-22-1, 72mg) were added to a solution of methyl4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (CAS No.:221316-61-6, 50 mg) in dichloromethane (1 mL) at 0° C., and the mixturewas stirred at room temperature for 15 hours. Then, 2 N hydrochloricacid was added to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained title compound was used for the next reactionwithout purification.

Reference Example 23:5-(Methoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 22 in methanol (1mL), and the mixture was stirred at 50° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, and the organiclayer was washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained titlecompound was used for the next reaction without purification.

Reference Example 24: 4,4-Dimethyl-6,7-dihydrothieno[3,2-c]pyran

To a solution of 2-(2-thienyl)ethanol (CAS No.: 160774-13-8, 400 mg) intoluene (4 mL), were added 2,2-dimethoxypropane (CAS No.: 77-76-9, 0.38mL) and iron(III) trifluoromethanesulfonate (CAS No.: 63295-48-7, 15.7mg), and the mixture was stirred at 70° C. for 17 hours. Triethylamine(0.22 mL) was added to the reaction solution, and the mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (284mg).

TLC: Rf 0.50 (ethyl acetate:n-hexane=1:9);

HPLC retention time (min): 1.07 (TFA);

MS (ESI, Pos.): 169 (M+H)⁺.

Reference Example 25:4,4-Dimethyl-6,7-dihydrothieno[3,2-c]pyran-2-carboxylic acid

A 1.6 M n-butyllithium-hexane solution (CAS No.: 109-72-8, 1.2 mL) wasadded to a solution of the compound (284 mg) prepared in ReferenceExample 24 in THF (10 mL) at −78° C., and the mixture was stirred at−78° C. for 2 hours. Thereafter, dry ice (1 g) was added to the reactionsolution, and the mixture was stirred at room temperature for 2 hours.Water and a 1 N aqueous sodium hydroxide solution were added to thereaction solution, and the aqueous layer was washed with methyltert-butyl ether. A 1 N aqueous hydrochloric acid solution was added tothe aqueous layer to adjust the pH of the aqueous layer to 1, followedby extraction with ethyl acetate. The organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate, thenconcentrated under reduced pressure to obtain the title compound (306mg).

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 213 (M+H)⁺.

Reference Example 26: 4H-Pyrano[3,4-d]thiazol-7-one

To a solution of 2-amino-4H-pyrano[3,4-d]thiazol-7-one (CAS No.:1253281-38-7, 873 mg) in THE (17.5 mL), was added n-pentyl nitrite (CASNo.: 463-04-7, 0.97 mL), and the mixture was stirred at 60° C. for 15hours. Water was added to the reaction solution, followed by extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (568 mg).

TLC: Rf 0.28 (ethyl acetate:n-hexane=1:2).

Reference Example 27: 7-Methylene-4H-pyrano[3,4-d]thiazole

A 1.3 N lithium bis(trimethylsilyl)amide THE solution (CAS No.:4039-32-1, 0.55 mL) was added to a solution ofmethyltriphenylphosphonium bromide (CAS No.: 1779-49-3, 253 mg) in THE(1.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour.Thereafter, the compound (100 mg) prepared in Reference Example 26 wasadded thereto, and the mixture was stirred at 0° C. for 40 minutes. Asaturated aqueous ammonium chloride solution was added to the reactionsolution, and the aqueous layer was subjected to extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (90 mg).

TLC: Rf 0.5 (ethyl acetate:n-hexane=1:2).

Reference Example 28: 7-Methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole

To a solution of the compound prepared in Reference Example 27 inmethanol (1.8 mL), was added 20% palladium hydroxide (10 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for7 hours. The reaction solution was filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (40 mg).

Reference Example 29:7-Methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2-carboxylic acid

A 1.6 M n-butyllithium hexane solution (0.16 mL) was added to a solutionof the compound (40 mg) prepared in Reference Example 28 in THE (2 mL)at −78° C., and the mixture was stirred at −78° C. for 1 hour.Thereafter, dry ice (300 mg) was added to the reaction solution, and themixture was stirred at room temperature for 1 hour. Water and a 1 Naqueous sodium hydroxide solution were added to the reaction solution,and the aqueous layer was washed with methyl tert-butyl ether. A 1 Naqueous hydrochloric acid solution was added to the aqueous layer toadjust the pH of the aqueous layer to 1, followed by extraction withethyl acetate. The organic layer was washed with saturated saline anddried over anhydrous sodium sulfate, then concentrated under reducedpressure to obtain the title compound (20 mg).

HPLC retention time (min): 0.76 (TFA);

MS (ESI, Pos.): 200 (M+H)⁺.

Reference Example 30: Methyl 5-hydroxy-2-thiophenecarboxylate

A 30% aqueous hydrogen peroxide solution (CAS No.: 7722-84-1, 0.11 mL)was added to a solution of thiophene-2-carboxylic acid methylester-5-boronic acid (CAS No.: 876189-21-8, 120 mg) in polyethyleneglycol 200 (CAS No.: 25322-68-3, 0.64 mL), and the mixture was stirredat room temperature for 2 hours. Water was added to the reactionsolution, followed by extraction with methyl tert-butyl ether. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (23 mg).

HPLC retention time (min): 0.84 (TFA);

MS (ESI, Pos.): 171 (M+Na)+.

Reference Example 31: Methyl 5-(difluoromethoxy)-2-thiophenecarboxylate

Chlorodifluoroacetic acid (CAS No.: 76-04-0, 0.027 mL) and cesiumcarbonate (CAS No.: 534-17-8, 142 mg) were added to a solution of thecompound (23 mg) prepared in Reference Example 30 in DMF (0.2 mL), andthe mixture was stirred at 100° C. for 10 minutes. Water was added tothe reaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (31 mg).

HPLC retention time (min): 1.06 (TFA);

MS (ESI, Pos.): 209 (M+H)⁺.

Reference Example 32: 5-(Difluoromethoxy)-2-thiophenecarboxylic acid

Methanol (0.1 mL) and a 1 N aqueous lithium hydroxide solution (CAS No.:1310-65-2, 0.2 mL) were added to a solution of the compound (31 mg)prepared in Reference Example 31 in THF (0.2 mL), and the mixture wasstirred at room temperature for 16 hours. A 1 N aqueous hydrochloricacid solution was added to the reaction solution to adjust the pH of theaqueous layer to 1, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline and dried over anhydroussodium sulfate, then concentrated under reduced pressure to obtain thetitle compound (21 mg).

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 195 (M+H)⁺.

Reference Example 33: Methyl3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate

Potassium hydroxide (CAS No.: 1310-58-3, 140 mg) and iodine (CAS No.:7553-56-2, 570 mg) were added to a solution of methyl1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS No.: 1246552-43-1, 185 mg)in DMF (2 mL), and the mixture was stirred at 0° C. for 1 hour. Then, 2N hydrochloric acid was added to the reaction solution, and a saturatedaqueous sodium thiosulfate solution was added thereto, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was washed with hexane andethyl acetate to obtain the title compound (180 mg).

Reference Example 34: Methyl3-(3-hydroxy-1-propyn-1-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylate

Propargyl alcohol (CAS No.: 107-19-7, 11 mg), copper(I) iodide (CAS No.:7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium(0) (CAS No.:14221-01-3, 15 mg), and triethylamine (0.09 mL) were added to a solutionof the compound (40 mg) prepared in Reference Example 33 in THE (1 mL),and the mixture was stirred at 60° C. for 1 hour. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (23 mg).

HPLC retention time (min): 0.84 (formic acid);

MS (ESI, Pos.): 237 (M+H)⁺.

Reference Example 35: Methyl3-(3-hydroxypropyl)-1H-thieno[3,2-c]pyrazole-5-carboxylate

To a solution of the compound (23 mg) prepared in Reference Example 34in methanol (1 mL), was added 20% palladium hydroxide (25 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for6 hours. The reaction solution was filtered and concentrated underreduced pressure, and the obtained title compound was used for the nextreaction without purification.

Reference Example 36: Methyl7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylate

Cyanomethylene tributylphosphorane (CAS No.: 157141-27-0, 27 mg) wasadded to a solution of the compound (18 mg) prepared in ReferenceExample 35 in toluene (0.5 mL), and the mixture was stirred at 60° C.for 1 hour. The mixture was purified by silica gel column chromatographyto obtain the title compound (10 mg).

¹H-NMR (CDCl₃): δ 7.85, 4.38, 3.83, 3.10, 2.73.

Reference Example 37:7,8-Dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 36 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 38: Methyl5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylate

Water (0.37 mL), 1-methyl-1H-pyrazole-4-boronic acid (CAS No.:847818-55-7, 48 mg), cesium carbonate (124 mg), andtetrakis(triphenylphosphine)palladium(0) (15 mg) were added to asolution of methyl 4-bromo-5-methylthiophene-2-carboxylate (CAS No.:237385-15-8, 30 mg) in toluene (0.75 mL), and the mixture was stirred at80° C. for 13 hours. The reaction solution was subjected to extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (10 mg).

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 237 (M+H)⁺.

Reference Example 39:5-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 38 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 40: Methyl2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylate

Sodium hydride (2.9 mg) and iodomethane (22 mg) were added to a solutionof methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate (CAS No.:873072-42-5, 20 mg) in DMF (1.0 mL), and the mixture was stirred at roomtemperature for 3 hours. Then, 2 N hydrochloric acid was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (10 mg).

¹H-NMR (CDCl₃): δ 7.69, 3.95, 3.89, 2.52.

Reference Example 41: 2,3-Dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylicacid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 40 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 42: Methyl2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylate

Cesium carbonate (7.2 g) and iodomethane (1.6 g) were added to asolution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (2.0 g) in THF(40 mL), and the mixture was stirred at room temperature for 3 hours.Then, 2 N hydrochloric acid was added to the reaction solution, followedby extraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (1.05 g).

¹H-NMR (CDCl₃): δ 7.70, 7.66, 4.06, 3.93.

Reference Example 43: 2-Methyl-2H-thieno[3,2-c]pyrazole-5-carboxylicacid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 42 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 44: Methyl2-cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylate

Cyclopropylboronic acid (CAS No.: 873072-42-5, 940 mg), sodium carbonate(CAS No.: 497-19-8, 1,200 mg), copper(II) acetate (CAS No.: 142-71-2,1.1 g), and 1,10-phenanthroline (CAS No.: 66-71-7, 1.1 g) were added toa solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (1.0 g) indichloroethane (20 mL), and the mixture was stirred at 70° C. for 15hours. Then, 1 N hydrochloric acid was added to the reaction solution,followed by extraction with ethyl acetate. The organic layer was washedwith saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (200mg).

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 223 (M+H)⁺.

Reference Example 45:2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 44 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 46: Methyl2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate

Sodium chlorodifluoroacetate (CAS No.: 1895-39-2, 2,100 mg) andpotassium carbonate (1,900 mg) were added to a solution of methyl1H-thieno[3,2-c]pyrazole-5-carboxylate (500 mg) in DMF (10 mL), and themixture was stirred at 100° C. for 20 hours. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (85 mg).

Reference Example 47:2-(Difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (20 mg) prepared in Reference Example 46 in methanol (1mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 48: (1) Methyl2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate and (2)methyl 1-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate

Cesium carbonate (720 mg) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (CAS No.: 6226-25-1, 510 mg) were added to asolution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (200 mg) inDMF (5 mL), and the mixture was stirred at room temperature for 15hours. Water was added to the reaction solution, followed by extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain 61 mg of the title compound (1) and 71 mg ofthe title compound (2).

-   -   (1) TLC: Rf 0.31 (ethyl acetate:n-hexane=1:3);    -   (2) TLC: Rf 0.34 (ethyl acetate:n-hexane=1:3).

Reference Example 49:2-(2,2,2-Trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (60 mg) prepared in Reference Example 48 (1) in methanol(1 mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 50:1-(2,2,2-Trifluoroethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solutionof the compound (60 mg) prepared in Reference Example 48 (2) in methanol(1 mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 Nhydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained title compound was used for thenext reaction without purification.

Reference Example 51: 2,3-Dimethyl-2H-thieno[3,2-c]pyrazole-5-carboxylicacid

The same procedures as in Reference Example 40→Reference Example 41 werecarried out using methyl 3-methyl-1H-thieno[3,2-c]pyrazole-5-carboxylate(CAS No.: 1379258-29-3) in place of methyl3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate to obtain the titlecompound.

Example 3:2-{[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-4-methyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one

DIPEA (0.016 mL) and HATU (10 mg) were added to a solution of thecompound (5 mg) prepared in Reference Example 12 and the compound (9.2mg) prepared in Reference Example 17 in DMA (0.25 mL), and the mixturewas stirred at room temperature for 3 hours. Water was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (4.7 mg).

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 476 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.44, 7.38, 7.28, 6.80, 4.10-3.96, 3.24, 3.18-3.03,3.01-2.87, 2.85, 2.71-2.57, 2.25-2.10, 2.10-1.96, 1.62-1.45.

Examples 3-1 to 3-14

The same procedure as in Example 3 was carried out using the compoundprepared in Reference Example 21, Reference Example 23, ReferenceExample 25, Reference Example 29, Reference Example 32, ReferenceExample 37, Reference Example 39, Reference Example 41, ReferenceExample 43, Reference Example 45, Reference Example 47, ReferenceExample 49, Reference Example 50, or Reference Example 51 in place ofthe compound prepared in Reference Example 17, and using the compoundprepared in Reference Example 12 or the compound prepared in ReferenceExample 10 in place of the compound prepared in Reference Example 12 toobtain each of the title compounds.

Example 3-1:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl)methanone

HPLC retention time (min): 0.74 (formic acid);

MS (ESI, Pos.): 400 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.46-9.25, 8.63-8.43, 8.40-8.30, 8.29-8.14,7.43-7.30, 6.97-6.83, 4.20-4.00, 3.99-3.65, 3.15-3.04, 3.04-2.79,2.77-2.57, 2.27-2.15, 2.14-1.98, 1.70-1.58, 1.58-1.48.

Example 3-2: Methyl2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

HPLC retention time (min): 0.97 (formic acid);

MS (ESI, Pos.): 506 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.49-7.44, 7.44-7.31, 6.86-6.78, 4.57-4.41,4.07-4.00, 3.67, 3.64, 3.20-3.05, 2.81, 2.71-2.45, 2.27-2.12, 2.09-1.95,1.64-1.54, 1.54-1.42.

Example 3-3:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,4-dimethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 435 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.23, 7.18, 6.63, 4.70, 4.11, 3.98, 3.95-3.83, 3.66,3.49, 2.89, 2.83, 2.69, 2.40-2.30, 2.17-2.08, 1.68-1.58, 1.48.

Example 3-4:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2-yl)-methanone

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 420 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.18, 6.63, 4.85-4.66, 4.25-4.17, 4.15-4.02, 3.85,3.55-3.46, 3.22, 3.03-2.55, 2.35, 2.13, 1.68-1.57, 1.29.

Example 3-5:[(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethoxy)-2-thienyl]methanone

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 415 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.32-7.28, 7.26-7.16, 6.67-6.61, 6.64, 4.69,4.16-4.06, 4.02, 3.87, 3.66, 3.66, 2.88, 2.70, 2.41-2.31, 2.18-2.08,1.69-1.58.

Example 3-6:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazol-2-yl)methanone

HPLC retention time (min): 0.92 (formic acid);

MS (ESI, Pos.): 473 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.63, 7.50-7.42, 7.41-7.28, 6.88-6.76, 4.32-4.21,4.10-3.95, 3.91-3.61, 3.07-2.96, 2.96-2.77, 2.68-2.58, 2.24-2.14,2.10-1.92, 1.69-1.55, 1.55-1.46.

Example 3-7:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl]methanone

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 487 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.05-7.98, 7.78-7.70, 7.59, 7.49-7.42, 7.42-7.32,6.87-6.76, 4.09-4.00, 3.88, 3.34-3.18, 2.94-2.75, 2.72-2.57, 2.48,2.26-2.14, 2.09-1.95, 1.64-1.55, 1.55-1.46.

Example 3-8:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2,3-dimethyl-2H-thieno[2,3-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 461 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.33-7.27, 7.26, 6.55, 4.80, 4.15-4.06, 4.02-3.93,3.91, 3.69, 2.88, 2.70, 2.55-2.47, 2.39-2.24, 2.18-2.02, 1.69-1.61.

Example 3-9:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.87 (TFA);

MS (ESI, Pos.): 447 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.57, 7.43, 7.33-7.27, 6.54, 4.83, 4.17-4.10,4.10-4.02, 3.94, 3.91-3.80, 3.69, 2.92, 2.71, 2.40-2.30, 2.18-2.04,1.70-1.61.

Example 3-10:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 473 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.67, 7.40, 7.34-7.27, 6.55, 4.92, 4.15-3.95, 3.93,3.90-3.78, 3.68, 2.90, 2.70, 2.39-2.28, 2.18-2.03, 1.71-1.65, 1.30-1.09.

Example 3-11:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 483 (M+H)⁺;

¹H-NMR (CDCl₃): δ 8.02, 7.48, 7.42, 7.35-7.27, 7.18, 6.71-6.49,4.14-3.98, 3.89, 3.69, 3.05-2.83, 2.74, 2.40-2.31, 2.15, 2.05, 1.68.

Example 3-12:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazol-5-yl]methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.97, 7.89-7.81, 7.52-7.43, 7.43-7.33, 6.90-6.72,5.48-5.31, 4.19-4.05, 4.04-3.92, 3.92-3.71, 3.01-2.63, 2.27-2.15,2.12-2.00, 1.66-1.57, 1.57-1.47.

Example 3-13:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 515 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.71, 7.42, 7.26, 6.55, 4.90, 4.16-3.97, 3.94, 3.86,3.68, 2.92, 2.72, 2.40-2.30, 2.15-2.07, 1.71-1.55.

Example 3-14:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.91 (formic acid);

MS (ESI, Pos.): 461 (M+H)⁺.

Reference Example 52:1-(5-((3aS,4R,6aR)-4-((6-Bromopyridazin-3-yl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)thiophen-2-yl)ethan-1-one

To a solution of the compound (10 mg) prepared in Reference Example 12in DMA (0.25 mL), were added 5-acetylthiophene-2-carboxylic acid (CAS:4066-41-5, 6.0 mg), DIPEA (0.030 mL), and HATU (20 mg), and the mixturewas stirred at room temperature for 3 hours. Water was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (15 mg).

Example 4:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-hydroxy-2-propanyl)-2-thienyl]methanone

To a solution of the compound (5 mg) prepared in Reference Example 52 inTHF (0.3 mL), was added 3 M methylmagnesium bromide (CAS: 75-16-1, 0.03mL), and the mixture was stirred at room temperature for 3 hours. Waterwas added to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (1.3 mg).

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 451 (M+H)⁺.

Example 5:[(3aS,4R,6aR)-4-[(6-Iodo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

Copper(I) iodide (3.0 mg), sodium iodide (CAS: 7681-82-5, 7.4 mg), andN,N′-dimethylethylenediamine (CAS: 110-70-3, 2.8 mg) were added to asolution of the compound (10 mg) prepared in Example 2 in 1,4 dioxane(0.1 mL), and the mixture was stirred at 110° C. for 18 hours. Anaqueous ammonia solution was added to the reaction solution, followed byextraction with dichloromethane. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (7.6 mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 455 (M+H)⁺.

Example 6:rel-{(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanoneracemic mixture

The same procedures as in Example 2→Reference Example 16 were carriedout using the compound prepared in Reference Example 12-1 in place ofthe compound prepared in Reference Example 12 to obtain the titlecompound.

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 421 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.55, 7.38, 7.19-7.10, 6.83, 4.86, 3.62, 3.27,3.22-3.05, 2.93, 2.81, 2.49-2.43, 2.06-1.96, 1.90-1.75, 1.58-1.45.

Examples 6-1 to 6-9

The same procedures as in Example 2→Reference Example 16 were carriedout using iodomethane or a corresponding halogen compound in place ofiodomethane, using 5-methyl-2-thiophenecarboxylic acid or acorresponding carboxylic acid in place of 5-methyl-2-thiophenecarboxylicacid, and using the compound prepared in Reference Example 12 or thecompound prepared in Reference Example 10-1 or the compound prepared inReference Example 12-1 in place of the compound prepared in ReferenceExample 12 to obtain each of the title compounds.

Example 6-1:rel-{(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(butyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanoneracemic mixture

HPLC retention time (min): 1.30 (formic acid);

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.51, 7.38, 7.12-7.05, 6.83, 4.66-4.58, 3.62, 3.47,3.45-3.43, 3.35-3.25, 3.22-3.05, 2.84, 2.45, 2.06-1.91, 1.83-1.75,1.54-1.40, 1.38-1.23, 1.18, 0.92.

Example 6-2:[(3aS,4R,6aR)-4-[Benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

HPLC retention time (min): 1.20 (TFA);

MS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.36-7.27, 7.21-7.16, 6.73, 6.48, 5.09, 4.60,3.92-3.73, 3.62, 2.82, 2.50, 2.29-2.21, 2.14-2.03, 1.89, 1.62-1.56.

Example 6-3:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.61-7.49, 7.32, 7.21-7.06, 4.95-4.81, 4.59, 3.87,3.82-3.56, 3.37-3.29, 3.14-3.03, 2.92, 2.09-1.93, 1.84-1.71, 1.57-1.45.

Example 6-4:rel-{(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)(3-methoxypropyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanoneracemic mixture

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 471 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.68-7.54, 7.52-7.42, 7.43-7.21, 7.25-7.15,4.71-4.59, 4.04-3.84, 3.64, 3.44-3.41, 3.31, 3.26, 3.24-3.15, 3.01-2.71,2.07-1.91, 1.85-1.68, 1.58-1.44.

Example 6-5:rel-{(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)(imidazo[2,1-b][1.3]thiazol-6-ylmethyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanoneracemic mixture

HPLC retention time (min): 0.98 (formic acid);

MS (ESI, Pos.): 535 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.88-7.75, 7.71-7.53, 7.53-7.17, 5.03-4.78, 4.65,4.03-3.59, 3.15-3.05, 2.97-2.74, 2.14-1.97, 1.96-1.79, 1.58-1.43.

Example 6-6:rel-{(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)(4-pyridinylmethyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanoneracemic mixture

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 490 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.61, 7.59, 7.53, 7.50-7.40, 7.24, 7.43-7.21,4.93-4.83, 4.80, 3.95, 3.87, 3.66, 3.23-3.08, 3.00, 2.88, 2.78, 2.67,2.55, 2.10, 1.99, 1.77-1.63, 1.62-1.45, 1.32-1.22, 1.18.

Example 6-7:rel-2-{[(6-Chloro-3-pyridazinyl)((3aS,4R,6aR)-2-{[5-(difluoromethyl)-2-thienyl]carbonyl}octahydrocyclopenta[c]pyrrol-4-yl)amino]methyl}benzonitrileracemic mixture

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 514 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.91-7.84, 7.62, 7.56-7.51, 7.50-7.40, 7.43-7.22,7.27-7.19, 4.95-4.85, 4.87-4.76, 4.02-3.87, 3.71, 3.42, 3.32-3.24,3.14-3.05, 2.96-2.67, 2.16-2.07, 2.06-1.94, 1.57-1.38.

Example 6-8:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(3-fluoropropyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 467 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.32-7.28, 6.79-6.72, 4.60, 4.48, 3.82, 3.71-3.52,2.91, 2.51, 2.20-2.02, 1.98, 1.66-1.58, 1.50, 1.33-1.19, 0.82.

Example 6-9:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

HPLC retention time (min): 0.93 (TFA);

MS (ESI, Pos.): 421 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.32-7.23, 6.78-6.65, 4.92-4.75, 4.01-3.85, 3.85-3.77,3.64, 2.98, 2.92-2.77, 2.50, 2.17-2.05, 1.91-1.79, 1.61-1.52.

Reference Example 53: rel-(3aS,6aR)-Hexahydrocyclopenta[c]pyrrol-4(1H)-one hydrochloride racemicmixture

The same procedures as in Reference Example 4→Reference Example 10 werecarried out using the compound prepared in Reference Example 1 in placeof the compound prepared in Reference Example 3 to obtain the titlecompound.

Reference Example 53-1: (3aS,6aR)-Hexahydrocyclopenta[c]pyrrol-4(1H)-one hydrochloride

The same procedure as in Reference Example 10 was carried out using thecompound prepared in Reference Example 3 in place of the compoundprepared in Reference Example 9 to obtain the title compound.

Reference Example 54: rel-(3aS,6aR)-2-(5-Methylthiophene-2-carbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-oneracemic mixture

DIPEA (22 mL) and HATU (17.6 g) were added to a solution of the compound(5.0 g) prepared in Reference Example 53 and5-methyl-2-thiophenecarboxylic acid (6.6 g) in DMA (100 mL), and themixture was stirred at room temperature for 3 hours. Then, 2 Nhydrochloric acid was added to the reaction solution, followed byextraction with dichloromethane. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (7.0 g).

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 250 (M+H)⁺.

Reference Example 54-1: (3aS,6aR)-2-(5-Methylthiophene-2-carbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one

The same procedure as in Reference Example 54 was carried out using thecompound prepared in Reference Example 53-1 in place of the compoundprepared in Reference Example 53 to obtain the title compound.

Reference Example 55:(rel-(3aS,4R,6aR)-4-(Cyclopropylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanoneracemic mixture

Cyclopropylamine (CAS: 765-30-0, 0.25 mL) and acetic acid (0.34 mL) wereadded to a solution of the compound (300 mg) prepared in ReferenceExample 54 in dichloromethane (10 mL), and the mixture was stirred atroom temperature for 10 minutes. Sodium triacetoxyborohydride (CAS:56553-60-7, 760 mg) was added thereto, and the mixture was stirred at40° C. for 3 hours. Then, 2 N sodium hydroxide was added to the reactionsolution, followed by extraction with dichloromethane. The organic layerwas washed with saturated saline, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (22 mg).

HPLC retention time (min): 0.78 (formic acid);

MS (ESI, Pos.): 291 (M+H)⁺.

Example 7:rel-{(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(cyclopropyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanoneracemic mixture

To a solution of the compound (20 mg) prepared in Reference Example 55in tert-amyl alcohol (CAS: 75-85-4, 0.3 mL), were added3-bromo-6-fluoropyridazine (CAS: 1353854-35-9, 39 mg) and DIPEA (0.083mL), and the mixture was stirred at 180° C. for 1 hour in a sealed tube.The reaction solution was concentrated under reduced pressure, and thenthe obtained residue was purified by silica gel column chromatography toobtain the title compound (1.0 mg).

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 447 (M+H)⁺.

Reference Example 56: (rel-(3aS, 4S,6aR)-4-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanoneracemic mixture

A 1 M lithium tri-sec-butylborohydride THF solution (8.5 mL) was addedto a solution of the compound (1.4 g) prepared in Reference Example 54in THE (42 mL) at −78° C., and the mixture was stirred at −78° C. for 1hour. A 35% aqueous hydrogen peroxide solution was slowly added to thereaction solution at 0° C. until foaming stopped, followed by extractionwith dichloromethane. The organic layer was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (600 mg).

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 252 (M+H)⁺.

Reference Example 57: rel-(3aS, 4S,6aR)-2-(5-Methylthiophene-2-carbonyl)octahydrocyclopenta[c]pyrrol-4-yl4-methylbenzenesulfonate racemic mixture

Triethylamine (4 mL), p-toluenesulfonyl chloride (4.1 g), andtrimethylamine hydrochloride (280 mg) were added to a solution of thecompound (3.6 g) prepared in Reference Example 56 in dichloromethane (70mL), and the mixture was stirred at room temperature. A saturatedaqueous sodium bicarbonate solution was added to the reaction solution,followed by extraction with dichloromethane. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (3.6g).

HPLC retention time (min): 1.16 (TFA);

MS (ESI, Pos.): 406 (M+H)⁺.

Example 8:rel[(3aS,4R,6aR)-4-(3-Chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanoneracemic mixture

To a solution of the compound (10 mg) prepared in Reference Example 57in THE (1 mL), were added 60% sodium hydride (3 mg) and3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (CAS No.: 2089649-63-6,7.7 mg), and the mixture was stirred at 50° C. for 20 hours. Water wasadded to the reaction solution, and then the resulting solution waspurified by reverse phase column chromatography to obtain the titlecompound (1.3 mg).

HPLC retention time (min): 0.90 (formic acid);

MS (ESI, Pos.): 389 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.45-7.38, 7.21-7.17, 6.88-6.80, 4.33-4.23,3.67-3.59, 3.54-3.44, 3.08-2.99, 2.92-2.77, 2.29-2.14, 2.08-1.94,1.94-1.76, 1.68-1.54, 1.57-1.42.

Examples 8-1 to 8-4

The same procedure as in Example 8 was carried out using a correspondingamine compound in place of3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine to obtain each of thetitle compounds.

Example 8-1:rel-[(3aS,4R,6aR)-4-(3-Chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanoneracemic mixture

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 387 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.69, 7.55, 7.33, 6.74, 6.46, 5.14-4.96, 4.01-3.86,3.73, 3.35-3.25, 3.13, 2.62, 2.51, 2.48-2.29, 1.80-1.65.

Example 8-2:rel-{(3aS,4R,6aR)-4-[(6-Chloro-4-methoxy-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanoneracemic mixture

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 393 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.35-7.28, 6.76-6.70, 6.56, 4.88, 4.34-4.26,4.15-4.02, 3.94-3.73, 3.73-3.60, 2.85, 2.74, 2.50, 2.46-2.29, 2.17-1.99,1.70-1.60.

Example 8-3:rel-((3aS,4R,6aR)-4-((6-Chloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanoneracemic mixture

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 362 (M+H)⁺.

Example 8-4:rel-((3aS,4R,6aR)-4-((4,6-Dichloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanoneracemic mixture

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 396 (M+H)⁺.

Reference Example 58:rel-tert-Butyl(3aS,4R,6aR)-4-((6-chloro-4-cyanopyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylateracemic mixture

The same procedures as in Reference Example 4→Reference Example5→Reference Example 6→Reference Example 7→Reference Example 8→ReferenceExample 9 were carried out using the compound prepared in ReferenceExample 1 in place of the compound prepared in Reference Example 3 andusing 3,6-dichloropyridazine-4-carbonitrile (CAS No.: 35857-93-3, 45 mg)in place of 3,6-dichloropyridazine to obtain the title compound.

Reference Example 59:rel-6-Chloro-3-(((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)amino)pyridazine-4-carbonitrileracemic mixture

To the compound (100 mg) prepared in Reference Example 58, was added 4 Nhydrochloric acid (1,4-dioxane solution, 3 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to obtain the title compound (5 mg).

Example 9:rel-6-Chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino)-4-pyridazinecarbonitrileracemic mixture

The same procedure as in Example 2 was carried out using the compoundprepared in Reference Example 59 in place of the compound prepared inReference Example 12 to obtain the title compound.

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 388 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.42, 7.37-7.27, 6.75, 5.11, 4.47-4.39, 4.05,3.99-3.82, 3.68, 2.91, 2.74, 2.53-2.50, 2.50-2.42, 2.21-1.98, 1.78-1.54.

Example 9-1

The same procedures as in Reference Example 9→Reference Example10→Example 1 were carried out using a corresponding halogen compound inplace of 3,6-dichloropyridazine and using a corresponding carboxylicacid in place of 5-(difluoromethyl)thiophene-2-carboxylic acid to obtainthe title compound.

Example 9-1:[(3aS,4R,6aR)-4-{[6-Chloro-4-(trifluoromethyl)-3-pyridazinyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 473 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.94-7.83, 7.37-7.24, 6.85-6.70, 4.60, 4.48-4.37,3.88, 3.82-3.63, 2.84-2.78, 2.97-2.67, 2.29-2.12, 2.10-1.98, 1.83-1.70,1.58-1.43.

Reference Example 60: (1)[(R)-4-[tert-Butyl(dimethyl)silyl]oxy-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone,and (2) [(3aR,6aS)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

Triethylamine (2.4 mL) and tert-butyldimethylsilyltrifluoromethanesulfonic acid (CAS No.: 69739-34-0, 2.0 mL) were addedto a solution of the compound (4.3 g) prepared in Reference Example 54-1in dichloromethane (86 mL), and the mixture was stirred at 40° C. for 2hours. A saturated aqueous sodium bicarbonate solution was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (1) (1.9 g) and the title compound (2) (1.0 g).

Reference Example 61: (3aR,6aS)-3a-Fluoro-2-(5-methylthiophene-2-carbonyl)-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-4-one

To a solution of the compound (1.9 g) prepared in Reference Example 60(1) in acetonitrile (38 mL), was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (CAS No.: 140681-55-6, 2.2 g), and the mixturewas stirred at room temperature for 20 minutes. The reaction solutionwas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to obtain the titlecompound (540 mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 268 (M+H)⁺.

Reference Example 62: [(3aR, 4S,6aS)-3a-Fluoro-4-hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

Sodium borohydride (CAS No.: 16940-66-2, 405 mg) was added to a solutionof the compound (1.9 g) prepared in Reference Example 61 in methanol (19mL) and THF (19 mL) at 0° C., and the mixture was stirred at 0° C. for 1hour. Water was added to the reaction solution, followed by extractionwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (872 mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 270 (M+H)⁺.

Reference Example 63:[(3aR,4R,6aS)-3a-Fluoro-2-(5-methylthiophene-2-carbonyl)-1.3.4.5.6.6a-hexahydro-1H-cyclopenta[c]pyrrol-4-yl]-4-methylbenzenesulfonate

Triethylamine (1.4 mL), p-toluenesulfonyl chloride (1.2 g), andtrimethylamine hydrochloride (154 mg) were added to a solution of thecompound (872 mg) prepared in Reference Example 62 in dichloromethane(13 mL), and the mixture was stirred at room temperature for 23 hours.Water was added to the reaction solution, followed by extraction withethyl acetate. The organic layer was washed with saturated saline, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatographyto obtain the title compound (1.0 g).

HPLC retention time (min): 1.16 (TFA);

MS (ESI, Pos.): 424 (M+H)⁺.

Reference Example 64:[(3aR,4R,6aS)-4-Azide-3a-fluoro-1.3.4.5.6.6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

Sodium azide (560 mg) was added to a solution of the compound (1.4 g)prepared in Reference Example 63 in dimethyl sulfoxide (13 mL), and themixture was stirred at 100° C. for 90 hours. Water was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedtitle compound was used for the next reaction without purification.

HPLC retention time (min): 1.08 (TFA);

MS (ESI, Pos.): 295 (M+H)⁺.

Reference Example 65:[(3aR,4R,6aS)-4-Amino-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

To a solution of the compound (892 mg) prepared in Reference Example 64in ethanol (18 mL), was added 20% palladium hydroxide (1.8 g), and themixture was stirred at room temperature for 15 hours under a hydrogenatmosphere. The reaction solution was filtered and concentrated underreduced pressure, and the obtained title compound was used for the nextreaction without purification.

HPLC retention time (min): 0.72 (TFA);

MS (ESI, Pos.): 269 (M+H)⁺.

Example 10:[(3aR,4R,6aS)-4-[(6-Bromopyridazin-3-yl)amino]-3a-fluoro-1.3.4.5.6.6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

DIPEA (0.91 mL) and 3-bromo-6-fluoropyridazine (619 mg) were added to asolution of the compound (470 mg) prepared in Reference Example 65 in2-methyl-2-butanol (9.4 mL), and the mixture was stirred at 180° C. for3 hours. Water was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (141 mg).

HPLC retention time (min): 1.00 (TFA);

MS (ESI, Pos.): 427 (M+H)⁺.

Reference Example 66:(3aR,4R,6aS)—N-(6-Bromo-3-pyridazinyl)-3a-fluorooctahydrocyclopenta[c]pyrrole-4-amine

Methanol (1 mL) and a 5 N aqueous sodium hydroxide solution (1 mL) wereadded to a solution of the compound (40 mg) prepared in Example 10 inTHE (2 mL), and the mixture was stirred at 50° C. for 16 hours. Waterwas added to the reaction solution, followed by extraction with ethylacetate. The organic layer was washed with saturated saline, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained title compound was used for the next reaction withoutpurification.

Example 11:[(3aR,4R,6aS)-4-[(6-Bromo-3-pyridazinyl)amino]3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.02 mL) and HATU (31 mg) were added to a solution of thecompound prepared in Reference Example 66 and6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (14 mg) in DMA (0.22mL), and the mixture was stirred at room temperature for 3 hours. Then,2 N hydrochloric acid was added to the reaction solution, followed byextraction with dichloromethane. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (22 mg).

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 467 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.29, 7.24-7.16, 6.59, 4.78, 4.75-4.67, 4.56, 4.28,4.22-4.08, 4.01-3.89, 3.61, 2.89, 2.51-2.40, 2.26-2.17, 1.86-1.75, 1.60,1.52-1.34.

Examples 11-1 to 11-3

The same procedure as in Example 11 was carried out using acorresponding carboxylic acid compound in place of6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid to obtain each ofthe title compounds.

Example 11-1:[(3aR,4R,6aS)-4-[(6-Bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 491 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.17, 7.64, 7.47, 7.30, 6.92, 4.55-4.41, 4.00, 2.89,2.73-2.68, 2.56-2.53, 2.29-2.16, 2.14-2.01, 1.87-1.72, 1.47-1.35,1.28-1.12, 1.12-1.01.

Example 11-2:[(3aR,4R,6aS)-4-[(6-Bromo-3-pyridazinyl)amino]3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(fluoromethyl)-2-thienyl]methanone

HPLC retention time (min): 0.92 (TFA);

MS (ESI, Pos.): 443 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.40, 7.31, 7.28, 7.10, 6.60, 5.54, 5.42, 4.84-4.74,4.62-4.48, 4.27-4.13, 4.01-3.93, 3.87, 3.61, 3.49, 3.00-2.83, 2.50,2.19, 2.28-2.14, 1.61-1.58, 1.53-1.36.

Example 11-3:[(3aR,4R,6aS)-4-[(6-Bromo-3-pyridazinyl)amino]3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethyl)-2-thienyl]methanone

HPLC retention time (min): 0.94 (TFA);

MS (ESI, Pos.): 457 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.36-7.27, 6.87, 6.59, 4.71, 4.59, 4.19, 4.01, 3.63,3.49, 3.28-3.17, 2.98-2.79, 2.57-2.41, 2.28-2.14, 1.87-1.73, 1.61-1.57,1.53-1.45.

Example 12:{(3aR,4R,6aS)-4-[(6-Chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

The same procedures as in Example 10→Reference Example 66→Example 11were carried out using 3,6-dichloropyridazine in place of3-bromo-6-fluoropyridazine and using a corresponding carboxylic acid inplace of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid to obtainthe title compound.

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 423 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.22-7.15, 6.70, 4.85, 4.71, 4.66-4.47, 4.27,4.19-4.09, 4.03-3.90, 3.61, 2.96-2.82, 2.45, 2.27-2.15, 1.88-1.66,1.58-1.37.

Reference Example 67: (3aS, 5R,6aR)-5-Fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-4-one

To a solution of the compound (1.3 g) prepared in Reference Example60(2) in acetonitrile (25 mL), was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.5 g), and the mixture was stirred at roomtemperature for 3 hours. The reaction solution was concentrated underreduced pressure, water was added to the obtained residue, followed byextraction with ethyl acetate. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (633 mg).

HPLC retention time (min): 0.81 (TFA);

MS (ESI, Pos.): 304 (M+H)⁺.

Reference Example 68: [(3aS, 4R, 5R,6aR)-5-Fluoro-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

Sodium borohydride (106 mg) was added to a solution of the compound (500mg) prepared in Reference Example 67 in methanol (10 mL) at 0° C., andthe mixture was stirred at 0° C. for 1 hour. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (200 mg).

Reference Example 69: [(3aS, 4R, 5R,6aR)-5-Fluoro-2-(5-methylthiophene-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-yl]4-methylbenzenesulfonate

DIPEA (0.23 mL), p-toluenesulfonyl chloride (127 mg), and trimethylaminehydrochloride (21 mg) were added to a solution of the compound (120 mg)prepared in Reference Example 68 in acetonitrile (1.2 mL), and themixture was stirred at room temperature for 24 hours. Water was added tothe reaction solution, followed by extraction with dichloromethane.After concentration, the obtained residue was purified by silica gelcolumn chromatography to obtain the title compound (190 mg).

HPLC retention time (min): 1.13 (TFA);

MS (ESI, Pos.): 424 (M+H)⁺.

Reference Example 70: [(3aS, 4S, 5R,6aR)-4-Azide-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

Sodium azide (145 mg) was added to a solution of the compound (190 mg)prepared in Reference Example 69 in dimethyl sulfoxide (0.8 mL), and themixture was stirred at 100° C. for 17 hours. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedtitle compound was used for the next reaction without purification.

HPLC retention time (min): 1.05 (TFA);

MS (ESI, Pos.): 295 (M+H)⁺.

Reference Example 71: [(3aS, 4S, 5R,6aR)-4-Amino-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

To a solution of the compound prepared in Reference Example 70 inethanol (2 mL), was added 20% palladium hydroxide (50 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for2 hours. The reaction solution was filtered and concentrated underreduced pressure, and the obtained title compound was used for the nextreaction without purification.

HPLC retention time (min): 0.75 (TFA);

MS (ESI, Pos.): 269 (M+H)⁺.

Example 13: [(3aS, 4S, 5R,6aR)-4-[(6-Bromopyridazin-3-yl)amino]-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

DIPEA (0.19 mL) and 3-bromo-6-fluoropyridazine (132 mg) were added to asolution of the compound (50 mg) prepared in Reference Example 71 in2-methyl-2-butanol (0.23 mL), and the mixture was stirred at 160° C. for1 hour. The reaction solution was purified by reverse phase columnchromatography to obtain the title compound (8.9 mg).

HPLC retention time (min): 0.94 (TFA);

MS (ESI, Pos.): 426 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.32, 7.28-7.26, 6.73, 6.62, 5.42-5.10, 4.89,4.51-4.38, 4.13-3.88, 3.63, 3.09-2.99, 2.82-2.75, 2.50, 1.95-1.77.

Reference Example 72: (3aS,6aR)-2-(6,7-Dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one

To a solution of the compound (2.8 g) prepared in Reference Example 53-1in DMA (230 mL), were added6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (4.6 g), DIPEA (13mL), and HATU (9.5 g), and the mixture was stirred at room temperaturefor 3 hours. Water was added to the reaction solution, followed byextraction with dichloromethane. The organic layer was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (4.1 g).

Reference Example 73: [(3aS,6aR)-6-{[Dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Triethylamine (2.8 mL) and tert-butyldimethylsilyltrifluoromethanesulfonate (2.3 mL) were added to a solution of thecompound (2.0 g) prepared in Reference Example 72 in dichloromethane (40mL) at 0° C., and the mixture was stirred at 50° C. for 22 hours. Asaturated aqueous sodium bicarbonate solution was added to the reactionsolution, followed by extraction with dichloromethane. The organic layerwas washed with saturated saline, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The obtained title compound wasused for the next reaction without purification.

Reference Example 74: (3aS, 5R,6aR)-2-(6,7-Dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-methylhexahydrocyclopenta[c]pyrrol-4(1H)-one

Iodomethane (9.5 g) and 1 M tetra-N-butylammonium fluoride (CAS No.429-41-4, 0.74 mL, THF solution) were added to a solution of thecompound prepared in Reference Example 73 in DMF (10 mL), and themixture was stirred at room temperature for 3 hours. The reactionsolution was concentrated under reduced pressure, water was added to theobtained residue, followed by extraction with ethyl acetate. The organiclayer was washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography to obtain the titlecompound (100 mg).

Example 14: [(3aS, 4R, 5R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

The same procedures as in Reference Example 62→Reference Example63→Reference Example 64→Reference Example 65→Example 10 were carried outusing the compound prepared in Reference Example 74 in place of thecompound prepared in Reference Example 61 to obtain the title compound.

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.33-7.28, 7.13, 6.65-6.58, 5.21, 4.70, 4.04-3.83,3.66, 2.93-2.85, 2.76, 2.55, 1.88-1.69, 0.95.

Reference Example 75: (3aS,6aR)-2-(6,7-Dihydro-4H-thieno[3,2-c]pyran-2-carbonyl)spiro[3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-5,1′-cyclopropan]-4-one

To a solution of the compound (300 mg) prepared in Reference Example 72in dimethyl sulfoxide (7.5 mL), were added1,8-diazabicyclo[5.4.0]undec-7-ene (CAS No.: 6674-22-2, 0.31 mL) anddiphenyl vinyl sulfonium triflate (CAS No.: 247129-88-0, 410 mg), andthe mixture was stirred at room temperature for 1 hour. Water and a 1 Naqueous hydrochloric acid solution were added to the reaction solution,followed by extraction with ethyl acetate. The organic layer was washedwith saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (100mg).

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 318 (M+H)⁺.

Reference Example 76:[(3aS,4R,6aR)-4-Hydroxyspiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1′-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Sodium borohydride (25 mg) was added to a solution of the compound (138mg) prepared in Reference Example 75 in methanol (2.8 mL) at 0° C., andthe mixture was stirred at 0° C. for 30 minutes. Water was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (95 mg).

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 320 (M+H)⁺.

Reference Example 77: [(3aS, 4S,6aR)-4-Azidospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1′-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Triphenylphosphine (CAS No.: 603-35-0, 102 mg), a 2.2 M diethylazodicarboxylate solution (CAS No.: 1972-28-7, 0.18 mL), anddiphenylphosphoryl azide (CAS No.: 26386-88-9, 82 mg) were added to asolution of the compound (95 mg) prepared in Reference Example 76 in THE(0.2 mL), and the mixture was stirred at room temperature for 30minutes. The reaction solution was purified by silica gel columnchromatography to obtain the title compound (43 mg).

HPLC retention time (min): 1.08 (TFA);

MS (ESI, Pos.): 345 (M+H)⁺.

Reference Example 78: [(3aS, 4S,6aR)-4-Aminospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1′-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

To a solution of the compound (43 mg) prepared in Reference Example 77in methanol (1 mL), was added 20% palladium hydroxide (20 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for30 minutes. The reaction solution was filtered, concentrated underreduced pressure, and purified by silica gel column chromatography toobtain the title compound (20 mg).

HPLC retention time (min): 0.73 (TFA);

MS (ESI, Pos.): 319 (M+H)⁺.

Example 15: [(3aS, 4S,6aR)-4-[(6-Bromopyridazin-3-yl)amino]spiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1′-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.92 mL) and 3-bromo-6-fluoropyridazine (18.9 mg) were added to asolution of the compound (17 mg) prepared in Reference Example 78 in2-methyl-2-butanol (0.5 mL), and the mixture was stirred at 180° C. for4 hours. Water was added to the reaction solution, followed byextraction with dichloromethane. The organic layer was purified bysilica gel column chromatography to obtain the title compound (13 mg).

HPLC retention time (min): 0.97 (TFA);

MS (ESI, Pos.): 477 (M+H)⁺;

¹H-NMR (CD₃OD): δ 7.37, 7.34-7.18, 6.84, 4.68, 4.12-3.91, 3.80, 2.97,2.93-2.81, 2.36, 2.07-1.95, 1.50, 1.41-1.17, 0.74-0.65, 0.60, 0.53-0.35.

Reference Example 79: 2-Methyl-2-propanylrel-[(3aS,4R,6aR)-2-benzyl-6-oxooctahydrocyclopenta[c]pyrrol-4-yl]carbamateracemic mixture

tert-Butyl N-(4-oxocyclopenta-2-en-1-yl)carbamate (CAS No.: 657396-97-9,17 g) and trifluoroacetic acid (58 mg) were added to a dichloromethanesolution (20 mL) ofN-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.6 g), and themixture was stirred at room temperature for 16 hours. Triethylamine (430mg) was added to the reaction solution, and the mixture was concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (300 mg).

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 331 (M+H)⁺.

Reference Example 80: 2-Methyl-2-propanylrel-[(3aS,4R,6aR)-2-benzyl-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamateracemic mixture

Bis(2-methoxyethyl)aminosulfur trifluoride (CAS No.: 202289-38-1, 1.2 g)was added to a solution of the compound (300 mg) prepared in ReferenceExample 79 in dichloromethane (5 mL) at 0° C., and the mixture wasstirred at room temperature for 15 hours. A saturated aqueous sodiumbicarbonate solution was added to the reaction solution, followed byextraction with dichloromethane. The mixture was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (120 mg).

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 353 (M+H)⁺.

Reference Example 81: 2-Methyl-2-propanylrel-[(3aS,4R,6aR)-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamateracemic mixture

To a solution of the compound (120 mg) prepared in Reference Example 80in ethanol (10 mL), was added 20% palladium hydroxide (120 mg), and themixture was stirred under a hydrogen atmosphere at room temperature for2 hours. The reaction solution was filtered and concentrated underreduced pressure. The obtained residue was used for the next reactionwithout purification.

Reference Example 82: 2-Methyl-2-propanylrel-[(3aS,4R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamateracemic mixture

To a solution of the compound prepared in Reference Example 81 in DMA (3mL), were added 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (112mg), DIPEA (0.26 mL), and HATU (210 mg), and the mixture was stirred atroom temperature for 3 hours. Water was added to the reaction solution,followed by extraction with dichloromethane. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (100mg).

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 429 (M+H)⁺.

Reference Example 83:rel-[(3aR,6R,6aS)-6-Amino-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanoneracemic mixture

To the compound (100 mg) prepared in Reference Example 82, was added 4 Nhydrochloric acid (1,4-dioxane solution, 3 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure to obtain the title compound (80mg).

Example 16:[(3aR,6R,6aS)-6-[(6-Bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.24 mL) and 3,6-dibromopyridazine (120 mg) were added to asolution of the compound (80 mg) prepared in Reference Example 83 in DMA(1 mL), and the mixture was stirred at 160° C. for 1 hour. Water wasadded to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography, and then two diastereomers were separated bysupercritical fluid chromatography (CHIRALPAK IC, CO2:methanol=70:30) toobtain a low-polarity substance (19 mg).

HPLC retention time (min): 1.00 (TFA);

MS (ESI, Pos.): 485 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 7.54-7.45, 7.36-7.35, 7.40-7.32, 6.85, 4.62,4.23-4.15, 3.88, 3.57-3.50, 3.38-3.31, 3.31-3.16, 2.99-2.88, 2.83,2.30-2.17.

Reference Example 84: 2-Bromo-5-[2-(2-fluoroethoxy)ethyl]thiophene

To a solution of 2-(5-bromothiophen-2-yl)ethan-1-ol (CAS No.:57070-78-7, 653 mg) in dimethylacetamide (15 mL), were added1-iodo-2-fluoroethane (CAS No.: 762-51-6, 1.52 mL) and sodium hydride(757 mg), and the mixture was stirred at room temperature for 17 hours.Thereafter, the mixture was stirred at 60° C. for 24 hours. Water wasadded to the reaction solution, followed by extraction with a mixedsolvent of ethyl acetate and n-hexane. The organic layer was washed withwater, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (396 mg).

HPLC retention time (min): 0.828 (TFA);

¹H-NMR (CDCl₃): δ 6.86, 6.61, 4.66-4.61, 4.54-4.49, 3.77-3.66, 3.04.

Reference Example 85: 5-[2-(2-Fluoroethoxy)ethyl]-2-thiophene carboxylicacid

Water (0.135 mL),trans-bis(acetato)bis[2-(di-O-tolylphosphino)benzyl]dipalladium(II) (CASNo.: 172418-32-5, 141 mg), DBU (0.673 mL), tri-tert-butylphosphoniumtetrafluoroborate (CAS No.: 131274-22-1, 43 mg), and molybdenumhexacarbonyl (CAS No.: 13939-06-5, 595 mg) were added to a solution ofthe compound (396 mg) prepared in Reference Example 84 in THF (1 mL).The reaction solution was heated at 120° C. for 1 hour. A 1 M aqueoushydrochloric acid solution and ethyl acetate were added to the reactionsolution, and the mixture was filtered. The organic layer was washedwith water, then dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (190 mg).

¹H-NMR (CDCl₃): δ 7.72, 6.91, 4.72-4.61, 4.55-4.49, 3.84-3.68, 3.15,2.50.

Reference Example 86:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone

DIPEA (0.024 mL) and 1H-benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate (hereinafter, PyBOP, 22 mg, CAS No.: 128625-52-5)were added to a solution of the compound (10 mg) prepared in ReferenceExample 12 and the compound (9.2 mg) prepared in Reference Example 85 inDMF (1.0 mL), and the mixture was stirred at room temperature for 1hour. Water was added to the reaction solution, followed by extractionwith dichloromethane. The organic layer was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (5.0 mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 483 (M+H)⁺.

Example 17:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone

Sodium hydride (4.1 mg) was added to a solution of the compound (5.0 mg)prepared in Reference Example 86 in DMF (1.0 mL). After stirring at roomtemperature for 15 minutes, iodomethane (0.003 mL) was added thereto,and the mixture was further stirred at room temperature for 1 hour.Water was added to the reaction solution, followed by extraction withdichloromethane. The organic layer was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (3.9 mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.34-7.27, 6.82, 6.70, 4.84, 4.64-4.61, 4.53-4.49,3.91, 3.83, 3.80-3.63, 3.11, 2.98, 2.92-2.77, 2.17-2.08, 1.90-1.80.

Reference Example 87: 5-(2-Fluoroethoxy)-2-thiophenecarboxylic acid

Sodium hydride (1,313 mg) was added to a solution of 2-fluoroethanol(CAS No.: 371-62-0, 1,578 mg) in DMA (15 mL) at room temperature, andthen 5-fluorothiophene-2-carboxylic acid (CAS No.: 4377-58-6, 600 mg)was added thereto. The reaction solution was stirred at 100° C. for 2days. Water was added to the reaction solution, followed by extractionwith a mixed solvent of ethyl acetate and n-hexane. The organic layerwas washed with water, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was dissolvedin methanol (4 mL), trimethylsilyldiazomethane (CAS No.: 18107-18-1, 1mL) was added thereto, and the mixture was stirred at room temperaturefor 1 hour. The reaction solution was purified by silica gel columnchromatography to obtain a methyl ester compound (60 mg). The methylester compound (60 mg) thus obtained was dissolved in methanol (4 mL),and then a 2 M aqueous sodium hydroxide solution (1.5 mL) was addedthereto. The reaction solution was stirred at 50° C. for 18 hours. Then,1 M hydrochloric acid was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed with waterand dried over anhydrous sodium sulfate, then concentrated under reducedpressure to obtain the title compound (57 mg).

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 191 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.53, 6.28, 4.84-4.79, 4.72-4.67, 4.38-4.27.

Reference Example 88:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone

DIPEA (0.024 mL) and PyBOP (22 mg) were added to a solution of thecompound (10 mg) prepared in Reference Example 12 and the compound (8.1mg) prepared in Reference Example 87 in DMF (1.0 mL), and the mixturewas stirred at room temperature for 1 hour. Water was added to thereaction solution, followed by extraction with dichloromethane. Theorganic layer was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (7.0 mg).

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 455 (M+H)⁺.

Example 18:[(3aS,4R,6aR)-4-[(6-Bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone

Sodium hydride (6.1 mg) was added to a solution of the compound (7.0 mg)prepared in Reference Example 88 in DMF (1.0 mL), and the mixture wasstirred at room temperature for 15 minutes. Thereafter, iodomethane(0.005 mL) was added thereto, and the mixture was further stirred atroom temperature for 1 hour. Water was added to the reaction solution,followed by extraction with dichloromethane. The organic layer waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to obtain the title compound (3.9mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 469 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.28, 7.19, 6.71, 6.24, 4.91-4.78, 4.71-4.66,4.37-4.33, 4.30-4.26, 3.95-3.78, 3.63, 2.98, 2.92-2.77, 2.17-2.09,1.91-1.80, 1.60.

Reference Example 89:2-{2-[(6-Bromo-3-pyridazinyl){(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino]ethoxy}ethyl4-methylbenzenesulfonate

Sodium hydride (88 mg) was added to a solution of the compound (300 mg)prepared in Example 2 in DMF (7.4 mL), and the mixture was stirred atroom temperature for 30 minutes. Diethylene glycol ditosylate (CAS No.:7460-82-4, 305 mg) was then added thereto, and the mixture was stirredat room temperature for 4 hours. An aqueous sodium bicarbonate solutionwas added to the reaction solution, followed by extraction withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to obtain thetitle compound (100 mg).

HPLC retention time (min): 1.18 (TFA);

MS (ESI, Pos.): 649 (M+H)⁺.

Example 19:[(3aS,4R,6aR)-4-{(6-Bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

Potassium fluoride (27 mg) and4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (CAS No.:23978-09-8, 174 mg) were added to a solution of the compound (100 mg)prepared in Reference Example 89 in acetonitrile (1.5 mL), and themixture was stirred at 80° C. for 40 minutes. The reaction solution wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography to obtain the titlecompound (41.6 mg).

HPLC retention time (min): 1.05 (TFA);

MS (ESI, Pos.): 497 (M+H)⁺;

¹H-NMR (CDCl₃): δ 7.37-7.30, 7.28-7.21, 6.85, 6.73, 4.60-4.53,4.48-4.41, 4.32-4.23, 3.89, 3.87-3.79, 3.78-3.61, 3.04-2.83, 2.50,2.20-2.01, 1.98-1.87.

Pharmacological Experimental Example 1: Evaluation of ABHD6 EnzymeInhibitory Activity

First, 1-arachidonoyl glycerol (Cayman Chemical) as a substrate wasprepared with an assay buffer containing 50 mM tris-HCl (pH 7.4), 100 mMNaCl, and 0.05% BSA, so as to have a final concentration of 10 μmol/L.Then, a compound was added therein so as to have a final concentrationof 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol/L (DMSO:final concentration of 0.3%). In addition, solutions to which DMSO wasadded so as to have a final concentration of 0.3% were prepared as agroup to which the compound was not added. The enzyme reaction wasstarted by adding recombinant human ABHD6 (33-337) prepared with thesame assay buffer to a mixed solution of the substrate and the compoundso as to have a final concentration of 300 μg/mL. The recombinant humanABHD6 (33-337) was a GST-tagged ABHD6, and one which was expressed in E.coli, then purified with a Glutathione-Sepharose 4B resin, and thenconcentrated was used. The enzyme reaction was carried out at roomtemperature using a 384-well microplate made of polypropylene, and wellsto which no enzyme was added were designated as a blank group.

One hour after the start of the enzyme reaction, methanol containing, asan internal standard substance, arachidonic acid-d8 (Cayman Chemical)and 1% formic acid was added to stop enzymatic reaction. The upper partof the enzyme reaction plate was sealed with aluminum, andcentrifugation was performed at 560 g for 5 minutes at room temperature.Then, arachidonic acid as an enzyme reaction product and arachidonicacid-ds as the internal standard substance were quantified withRapidFire (registered trademark)-Mass Spectrometry system. The ratio ofthe quantitative values of the respective substances was taken, and theinhibition rate of arachidonic acid production at each compoundconcentration was calculated with the average of the blank group as 100%inhibition and the average of the group to which the compound was notadded as 0% inhibition to determine the IC₅₀ value.

From the above pharmacological experiments, it was found that thecompound of the present disclosure had potent ABHD6 inhibitory activity.For example, the IC₅₀ values of some compounds of the present disclosureare shown in Table 1 below.

TABLE 1 Example No. IC₅₀ (μM) 1 0.001 1-2 0.001 1-4 0.001 2 <0.001 2-10.001 2-6 0.002  2-14 0.002 3 0.005 3-6 0.002 3-9 0.001  3-10 0.001 50.001 6 0.002 6-2 0.001 8-1 0.001 9 0.002 10 <0.001 12 0.001 15 0.001 160.001

Pharmacological Experimental Example 2: Measurement of Binding Affinityfor Human ABHD6

The binding affinity of the test compound for human ABHD6 was measuredusing bioluminescence resonance energy transfer (hereinafter,abbreviated as BRET) as an index. The bioluminescence resonance energytransfer is induced by the proximity of a probe molecule and aNanoLuc-human ABHD6 fusion protein, which is caused by allowing afluorescent probe molecule and a test compound to act in a competitivemanner using HEK293 cells forcibly expressing the NanoLuc-human ABHD6fusion protein.

<Compound Treatment>

The test compound and the compound described in Example 2 as a controlsubstance were each dissolved in dimethyl sulfoxide (DMSO) to prepare a10 mmol/L solution. The prepared 10 mmol/L solution was thawed at thetime of use, serially diluted with DMSO, and subjected to an experiment.

<Cell Culture>

HEK293 cells expressing a NanoLuc-human ABHD6 fusion protein werestatically cultured at 37° C. in the presence of 5% CO₂ usinginactivated (56° C., 30 min) 9.8 vol % non-dialyzed-FBS (containing 0.5vol % GENETICIN and 1% penicillin-streptomycin). The subculture wasperformed by the following method.

The culture medium was removed, and the cells were washed once withphosphate buffered saline without Ca²⁺ and Mg²⁺. An appropriate amountof trypsin-EDTA was added, and the cells were incubated at roomtemperature. After the cells were detached, a culture medium in a volume10-fold the volume of trypsin-EDTA (0.05%) was added to stop an enzymereaction. The cells were collected in a centrifuge tube, and centrifugedat room temperature for 3 minutes at 120 g, and the supernatant wasremoved. The cells were suspended in an appropriate amount of culturemedium and seeded in a culture flask.

HEK293 cells expressing a NanoLuc-human ABHD6 fusion protein wereprepared, and then cryopreserved so as to be 5.0×10⁶ cells/mL/vial inCELLBANKER2, and the cells were subjected to an experiment. HBSS (+)containing 20 mmol/L HEPES (pH 7.3) and 0.1% BSA was prepared and usedas an assay buffer. The cells were thawed and suspended in the assaybuffer to prepare a cell suspension of 2×10⁵ cells/mL. The cellsuspension (25 L) was added to a 384-well assay plate to which a testcompound has been added in advance, to start the reaction. The plate wasallowed to stand at 37° C. for 30 minutes in the presence of 5% CO₂.Then, a probe molecule (10 mmol/L in DMSO) having a fluorophore wasdiluted with the assay buffer so as to have a final concentration of 100nmol/L, and added to the assay plate in an amount of 15 μL each.Further, this was allowed to stand at 37° C. for 30 minutes in thepresence of 5% CO₂. Then, a Nano-Glo (registered trademark) Vivazine(trademark) substrate (Promega Corporation) was diluted with the assaybuffer according to the method described in the protocol, and added tothe assay plate in an amount of 10 μL each, and this was allowed tostand at room temperature for 1 hour. Thereafter, the luminescence andfluorescence intensity were measured using a GloMax (registeredtrademark) discover system. The ratio between the emission intensitythrough the 450 nm bandpass filter and the fluorescence intensitythrough the 600 nm longpass filter was defined as the measured value ofeach sample. The measured value of the group containing the controlsubstance at a final concentration of 30 μmol/L was defined as 100%inhibition. The measured value of the group not containing the compoundwas defined as 0% inhibition. The IC₅₀ value of the test compound wasdetermined from the measured value at each test compound concentration.

In the cell evaluation system, it was observed that the compound of thepresent disclosure had potent ABHD6 binding activity. For example, theIC₅₀ values of some compounds of the present disclosure are shown inTable 2 below.

TABLE 2 Example No. IC₅₀ (μM) 1 0.011 1-2 0.005 1-4 0.002 2 0.001 2-10.003 2-6 0.025  2-14 0.016 3 0.062 3-6 0.006 3-9 0.005  3-10 0.002 50.003 6 0.005 6-2 0.001 8-1 0.005 9 0.008 10 0.002 12 0.001 15 0.001 160.004

Pharmacological Experimental Example 3: Evaluation of ABHD6 Selectivity

A fluorescent probe molecule and a test compound were allowed to actusing a rat brain membrane fraction, followed by protein separation byelectrophoresis. Then, the binding affinity of the test compound wasmeasured using the fluorescence intensity of ABHD6, MAGL, and FAAH as anindex.

<Compound Treatment>

The test compound was dissolved in dimethyl sulfoxide (DMSO) to preparea 10 mmol/L solution. The prepared 10 mmol/L solution was thawed at thetime of use, serially diluted with DMSO, and adjusted to a concentration50 times higher than the final concentration.

<Preparation of Rat Brain Membrane Fraction>

The rat was exsanguinated under anesthesia, and then the brain thereofwas extracted. Then, 1 mL of ice-cooled phosphate buffered saline (PBS,pH 7.5) was added per 200 mg of the brain, and this was homogenized by ahomogenizer. The homogenate solution was centrifuged at 1,000 g and 4°C. for 10 minutes, and then the supernatant was collected. The obtainedsupernatant was centrifuged at 100,000 g and 4° C. for 45 minutes,ice-cold PBS was added to the sediment, and the mixture was resuspendedto obtain a membrane fraction. The protein concentration in the preparedbrain membrane fraction solution was quantified, and the fractionsolution was stored in a freezer at −80° C. until use.

<ABPP>

The brain membrane fraction solution was prepared to 3 mg/mL with PBS.Then, 1 μL of DMSO or the compound solution was added to 50 μL of the 3mg/mL membrane fraction solution, and this was reacted at 37° C. for 30minutes. Thereafter, 1 μL of a probe molecule (ActivX (trade name)TAMRA-FP Serine Hydrolase Probe, final concentration: 1 μmol/L, DMSOsolution) having a fluorophore was added thereto, and this was reactedat room temperature for 30 minutes. The reaction was stopped with a 4×sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)loading buffer. The sample was heat-treated at 95° C. for 5 minutes, andthen protein separation was performed by SDS-PAGE using a 10% acrylamidegel. In the gel after SDS-PAGE, fluorescence was visualized with achemiluminescence imaging system.

In each band of ABHD6, MAGL, and FAAH, the IC₅₀ value of the testcompound was determined from the fluorescence intensity at each testcompound concentration with the fluorescence band intensity of thecontrol group (DMSO-treated group) as 0% inhibition. As a result, it wasfound that the compound of the present disclosure had selectiveinhibitory activity on ABHD6 against MAGL and FAAH.

Pharmacological Experimental Example 4: Analgesic Effect on SodiumMonoiodoacetate-Induced Model Rat

The analgesic effect of the compound of the present disclosure wasevaluated using a sodium monoiodoacetate (hereinafter, abbreviated asMIA) (Sigma-Aldrich Japan)-induced model rat.

(1) Preparation of MIA-Induced Model Rat

The periphery of the knee of the right hind limb of the rat was shavedunder isoflurane anesthesia, and 25 μL of a 120 mg/mL MIA solution wasadministered into the joint space of the right hind limb using a glasssyringe with a 29 G injection needle (BD Roads, Becton, Dickinson andCompany, Japan). The normal control group received 25 μL ofphysiological saline.

(2) Group Configuration and Grouping

Rats were divided into groups consisting of a normal control group, anonset control group, a test substance administration group, and atramadol administration group or a morphine administration group. Exceptfor the normal control group, the right hind limb load weight ratio(measurement method will be described later) of the MIA-induced 13 or 14days later model rat prepared by the method of (1) above was measured,and the rats were divided into groups so that the right hind limb loadweight ratio was not biased in each group.

(3) Administration of Test Substance, Tramadol, or Morphine

The compound of the present disclosure as a test substance was dissolvedin a solubilizing medium (7:3 solution of Kolliphor: PEG) to prepare a0.4 or 8 mg/mL solution. The prepared solution was diluted four timeswith distilled water to prepare a 0.1 or 2 mg/mL solution (finalconcentration of solubilizing medium: 25%). Tramadol as a positivecontrol drug was dissolved in physiological saline to prepare a 2 mg/mLsolution. Alternatively, morphine as a positive control drug wasdissolved in physiological saline to prepare a 0.6 mg/mL solution. Thetest substance was orally administered at 5 mL/kg 5 hours before theevaluation, and tramadol and morphine were subcutaneously administeredat 5 mL/kg 1 hour before the evaluation.

(4) Measurement of Right Hind Limb Load Weight Ratio

The load weights of the left and right hind limbs were measured using aLinton Incapacitance Tester (MJS Technology INC., UK). Specifically, therat was transferred to a dedicated cage on the Linton IncapacitanceTester, and the posture of the rat was adjusted so that the left andright hind limbs thereof separately ride on two pairs of weightmeasuring sensors. After confirming that the posture of the rat was notbiased left and right and front and back, the load weight of each of theleft and right hind limbs was measured for 3 seconds. The measurement ofthe load weight was repeated three times per individual rat. In order toobtain a stable measured value, the rat was placed in a dedicated cagefor 5 days or more and acclimated for 20 minutes or more between the dayof MIA induction and 14 days after induction. Furthermore, the rat wasalso acclimated for about 10 minutes immediately before the load weightmeasurement to measure the load weight. The load weights of left andright hind limbs before grouping 14 days after MIA induction, and thenormal control group, the onset control group, the test substanceadministration group (5 hours after administration), the tramadoladministration group (1 hour after administration), and the morphineadministration group (1 hour after administration) after 14 days weremeasured. The load weight ratio of the right hind limb in the loadweight of both hind limbs was calculated based on the average of loadweights of left and right hind limbs, from the following Formula 1. Theimprovement rate of the right hind limb load weight ratio at the time ofadministration of the compound of the present disclosure as a testsubstance was calculated based on the right hind limb load weight ratioof each group 14 days after MIA induction, from the following Formula 2.Then, the analgesic effect of the test substance (compound of thepresent disclosure) was evaluated.

Right hind limb load weight ratio B (%)={A _(R)/(A _(R) +A_(L))×100}  [Mathematical Formula 1]

-   -   A_(R): Load weight of right hind limb (average of values        obtained by measuring the same individual three times)    -   A_(L): Load weight of left hind limb (average of values obtained        by measuring the same individual three times)

Improvement rate of test substance (%)={1−(B _(T) −B _(C))/(B _(N) −B_(C))}×100  [Mathematical Formula 2]

-   -   B_(C): Average of right hind limb load weight ratios in normal        control group    -   B_(N): Average of right hind limb load weight ratios in onset        control group    -   B_(T): Average of right hind limb load weight ratios in test        substance administration group

As a result, it was found that the analgesic effect of the compound ofthe present disclosure was equivalent to or more than that of tramadoland morphine which are widely used as analgesics.

FORMULATION EXAMPLES

The following components are mixed by an ordinary method and compressedto obtain about 10,000 tablets containing 10 mg of the active ingredientin one tablet.

-   -   {(3aS,4R,6aR)-4-[(6-Chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone        . . . 100 g    -   Carboxymethylcellulose calcium (disintegrant) . . . 20 g    -   Magnesium stearate (lubricant) . . . 10 g    -   Microcrystalline cellulose . . . 870 g

INDUSTRIAL APPLICABILITY

The compound of the present disclosure has ABHD6 inhibitory activity,and thus a drug containing the compound of the present disclosure as anactive ingredient is useful as an agent for preventing and/or treating adisease associated with ABHD6.

1. A compound represented by general formula (I-A) or a pharmaceuticallyacceptable salt thereof:

wherein X¹ and X² each independently represent (1) CH, (2) CR^(X), or(3) N, provided that at least one of X¹ and X² represents N, R¹represents a halogen atom, R^(X) represents (1) a halogen atom, (2) aC1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group,(5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxygroup, or (10) a cyano group, R² represents (1) a halogen atom, (2) aC1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group,(5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxygroup, or (10) a cyano group, when m is 2 or more, a plurality of R²smay be the same or different, R³ represents (1) a hydrogen atom, (2) aC1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-memberedcyclic group, (5) —(C1-6 alkylene)-(3- to 10-membered cyclic group), (6)—(C1-6 haloalkylene)-(3- to 10-membered cyclic group), wherein one totwo carbon atoms in the C1-6 alkyl group, the C1-6 haloalkyl group, theC1-6 alkylene, and the C1-6 haloalkylene may be replaced with an oxygenatom or an optionally oxidized sulfur atom, the 3- to 10-membered cyclicgroup in R³ may be substituted with one to five R³⁰¹s, R³⁰¹ represents(1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4)a C1-4 haloalkyl group, (5) a C1-4 haloalkoxy group, (6) COOR³⁰², (7)CONR³⁰³R³⁰⁴, (8) a C3-6 cycloalkyl group, (9) a hydroxyl group, (10) anitro group, (11) a cyano group, (12) —NR³⁰⁵R³⁰⁶, (13) —SR³⁰⁷, (14)—SOR³⁰⁸, (15) —SO₂R³⁰⁹, or (16) an oxo group, when two or more R³⁰¹s aresubstituted, a plurality of R³⁰¹s may be the same or different, R³⁰²,R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, or R³⁰⁹ each independently represent(1) a hydrogen atom or (2) a C1-4 alkyl group, when R² represents (2) to(9) in R², and R³ represents a C1-6 alkyl group, R² and R³, togetherwith an atom to which R² and R³ are bonded, may form a 5- to 6-memberedcyclic group, R⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group,(3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxygroup, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) aC2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group, when n is 2 ormore, a plurality of R⁴s may be the same or different, when two R⁴spresent on the same carbon atom represent a C1-6 alkyl group, the twoR⁴s, together with a carbon atom to which the two R⁴s are bonded, mayform a C3-6 cycloalkyl group, ring 1 represents a 3- to 15-memberedcyclic group, R^(5-A) represents (1) a halogen atom, (2) a C1-6 alkylgroup, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinylgroup, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-to 6-membered cyclic group, (11) -L^(R5)-(3- to 6-membered cyclicgroup), (12) a hydroxyl group, (13) a nitro group, (14) a cyano group,(15) an oxo group, (16) —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵, or(19) —SO₂NR⁵⁰⁶R⁵⁰⁷, wherein one to two carbon atoms in the C1-6 alkylgroup, the C2-6 alkenyl group, the C2-6 alkynyl group, the C1-6 alkoxygroup, the C1-6 alkylthio group, the C1-6 alkylsulfinyl group, the C1-6alkylsulfonyl group, the C2-6 acyl group may be replaced with an oxygenatom or an optionally oxidized sulfur atom, when p is 2 or more, aplurality of R^(5-A)s may be the same or different, the groups (2) to(11) in R^(5-A) may be substituted with one to nine R⁵⁰⁸s, R⁵⁰⁸represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxygroup, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) ahydroxyl group, or (7) —NR⁵⁰⁹R⁵¹⁰, when two or more R⁵⁰⁸s aresubstituted, a plurality of R⁵⁰⁸s may be the same or different, L^(R5)represents (1) —O—, (2) —(C1-4 alkylene)-, (3) —O—(C1-4 alkylene)-, (4)—(C1-4 alkylene)-O—, (5) —NR⁵¹¹—, or (6) —SO₀₋₂—, R⁵⁰¹, R⁵⁰², R⁵⁰³,R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, R⁵⁰⁹, R⁵¹⁰, or R⁵¹¹ each independently represent(1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or(4) a C1-6 alkylsulfonyl group, m represents an integer of 0 to 2, nrepresents an integer of 0 to 5, and p represents an integer of 0 to 5.2. A compound represented by general formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein X¹ and X² each independently represent (1) CH, (2) CR^(X), or(3) N, provided that at least one of X¹ and X² represents N, R¹represents a halogen atom, R^(X) represents (1) a halogen atom, (2) aC1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group,(5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxygroup, or (10) a cyano group, R² represents (1) a halogen atom, (2) aC1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group,(5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxygroup, or (10) a cyano group, when m is 2 or more, a plurality of R²smay be the same or different, R³ represents (1) a hydrogen atom, (2) aC1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-memberedcyclic group, (5) —(C1-6 alkylene)-(3- to 10-membered cyclic group), (6)—(C1-6 haloalkylene)-(3- to 10-membered cyclic group), wherein one totwo carbon atoms in the C1-6 alkyl group, the C1-6 haloalkyl group, theC1-6 alkylene, and the C1-6 haloalkylene may be replaced with an oxygenatom or an optionally oxidized sulfur atom, the 3- to 10-membered cyclicgroup in R³ may be substituted with one to five R³⁰¹s, R³⁰¹ represents(1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4)a C1-4 haloalkyl group, (5) a C1-4 haloalkoxy group, (6) COOR³⁰², (7)CONR³⁰³R³⁰⁴, (8) a C3-6 cycloalkyl group, (9) a hydroxyl group, (10) anitro group, (11) a cyano group, (12) —NR³⁰⁵R³⁰⁶, (13) —SR³⁰⁷, (14)—SOR³⁰⁸, (15) —SO₂R³⁰⁹, or (16) an oxo group, when two or more R³⁰1s aresubstituted, a plurality of R³⁰¹s may be the same or different, R³⁰²,R³⁰³, R³⁰⁴, R³⁰⁵, R³⁰⁶, R³⁰⁷, R³⁰⁸, or R³⁰⁹ each independently represent(1) a hydrogen atom or (2) a C1-4 alkyl group, when R² represents (2) to(9) in R² and R³ represents a C1-6 alkyl group, R² and R³, together withan atom to which R² and R³ are bonded, may form a 5- to 6-memberedcyclic group, R⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group,(3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxygroup, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) aC2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group, when n is 2 ormore, a plurality of R⁴s may be the same or different, when two R⁴spresent on the same carbon atom represent a C1-6 alkyl group, the twoR⁴s, together with a carbon atom to which the two R⁴s are bonded, mayform a C3-6 cycloalkyl group, ring 1 represents a 3- to 15-memberedcyclic group, R⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group,(3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxygroup, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) aC1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-memberedcyclic group, (11) -L^(R5)-(3- to 6-membered cyclic group), (12) ahydroxyl group, (13) a nitro group, (14) a cyano group, (15) an oxogroup, (16) —NR⁵⁰¹R⁵⁰², (17) —COOR⁵⁰³, (18) —CONR⁵⁰⁴R⁵⁰⁵, or (19)—SO₂NR⁵⁰⁶R⁵⁰⁷, when p is 2 or more, a plurality of R⁵s may be the sameor different, the groups (2) to (11) in R⁵ may be substituted with oneto nine R⁵⁰⁸s, R⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkylgroup, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6cycloalkyl group, (6) a hydroxyl group, or (7) —NR⁵⁰⁹R⁵¹⁰, when two ormore R⁵⁰⁸s are substituted, a plurality of R⁵⁰⁸s may be the same ordifferent, L^(R5) represents (1) —O—, (2) —(C1-4 alkylene)-, (3)—O—(C1-4 alkylene)-, (4) —(C1-4 alkylene)-O—, (5) —NR⁵¹¹— or (6)—SO₀₋₂—, R⁵⁰¹, R⁵⁰², R⁵⁰³, R⁵⁰⁴, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, R⁵⁰⁹, R⁵¹⁰, or R⁵¹¹each independently represent (1) a hydrogen atom, (2) a C1-6 alkylgroup, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group, mrepresents an integer of 0 to 2, n represents an integer of 0 to 5, andp represents an integer of 0 to
 5. 3. The compound or thepharmaceutically acceptable salt thereof according to claim 1, whereinring 1 represents a ring structure selected from the group consisting ofthe following ring structures;

wherein the * mark represents a bonding position with a carbonyl group,and a hydrogen atom represented by NH may be replaced with R^(5-A). 4.The compound or the pharmaceutically acceptable salt thereof accordingto claim 2, wherein ring 1 represents a ring structure selected from thegroup consisting of the following ring structures;

wherein the * mark represents a bonding position with a carbonyl group,and a hydrogen atom represented by NH may be replaced with R⁵.
 5. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 1, wherein R^(5-A) is (1) a C1-6 alkyl group, (2) a C1-6 alkoxygroup, (3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy group, (5) acyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8)an oxo group, (9) a dimethylamino group, or (10) —COOCH₃.
 6. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 2, wherein R⁵ is (1) a C1-6 alkyl group, (2) a C1-6 alkoxy group,(3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy group, (5) acyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8)an oxo group, (9) a dimethylamino group, or (10) —COOCH₃.
 7. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 1, wherein R³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3)a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) —CH₂-Q, and Q is(1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.
 8. Thecompound or the pharmaceutically acceptable salt thereof according toclaim 1, wherein X¹ and X² are both N.
 9. The compound or thepharmaceutically acceptable salt thereof according to claim 1, whereinthe compound represented by general formula (I-A) or general formula (I)is a compound represented by general formula (I-1):

wherein R^(3-a) represents (1) a hydrogen atom, (2) a C1-6 alkyl group,(3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) —CH₂-Q, ring1-a represents a ring structure selected from the group consisting ofthe following ring structures;

wherein the * mark represents a bonding position with a carbonyl group,and a hydrogen atom represented by NH may be replaced with R^(5-a),R^(5-a) represents (1) a C1-6 alkyl group, (2) a C1-6 alkoxy group, (3)a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy group, (5) a cyclopropylgroup, (6) a furan ring, (7) an N-methylpyrazole ring, (8) an oxo group,(9) a dimethylamino group, or (10) —COOCH₃, and other symbols representthe same meaning as the symbols described in claim
 1. 10. The compoundor the pharmaceutically acceptable salt thereof according to claim 1,wherein the compound represented by general formula (I-A) or generalformula (I) is a compound selected from the group consisting of: (1){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone,(2){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone,(3)[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,(4)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,(5)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,(6)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,(7)[(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,(8)rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino)-4-pyridazinecarbonitrile,(9){(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,and (10)[(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone.11. A pharmaceutical composition comprising the compound or thepharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient, and a pharmaceutically acceptable carrier.
 12. Thepharmaceutical composition according to claim 11, which is an ABHD6inhibitor.
 13. The pharmaceutical composition according to claim 11,which is an agent for treating and/or preventing a disease associatedwith ABHD6.
 14. The pharmaceutical composition according to claim 13,wherein the disease associated with ABHD6 is pain, a neurologicaldisease, an inflammatory disease, an autoimmune disease, a metabolicdisease, or a malignant tumor.
 15. The pharmaceutical compositionaccording to claim 13, wherein the disease associated with ABHD6 ispain, and the pain is pain associated with osteoarthritis, cancer pain,pain associated with chemotherapy, chronic low back pain, low back painassociated with osteoporosis, fracture pain, pain associated withrheumatoid arthritis, neuropathic pain, post-herpetic pain, painassociated with diabetic neuropathy, pain associated with fibromyalgia,pain associated with pancreatitis, pain associated with interstitialcystitis or bladder pain syndrome, pain associated with endometriosis,pain associated with irritable bowel syndrome, migraine, or painassociated with pulpitis.
 16. The pharmaceutical composition accordingto claim 11, wherein the pharmaceutical composition is administered incombination with one or more selected from the group consisting ofacetaminophen, non-steroidal anti-inflammatory drugs, opioid drugs,antidepressant drugs, antiepileptic drugs, N-methyl-D-aspartateantagonists, muscle relaxants, antiarrhythmic drugs, steroid drugs, andbisphosphonate drugs.
 17. An agent for treating and/or preventing adisease associated with ABHD6, comprising the compound or thepharmaceutically acceptable salt thereof according to claim
 1. 18. Amethod for preventing and/or treating a disease associated with ABHD6,the method comprising administering the compound or the pharmaceuticallyacceptable salt thereof according to claim 1, or a pharmaceuticalcomposition comprising the compound or the pharmaceutically acceptablesalt thereof to a patient in need of prevention and/or treatment of adisease associated with ABHD6.
 19. A compound or a pharmaceuticallyacceptable salt thereof according to claim 1, for use in preventingand/or treating a disease associated with ABHD6.
 20. Use of the compoundor the pharmaceutically acceptable salt thereof according to claim 1, inthe manufacture of an agent for preventing and/or treating a diseaseassociated with ABHD6.